CN101646652A - Quinoline derivatives and pharmaceutical compositions comprising them for selectin inhibition - Google Patents

Quinoline derivatives and pharmaceutical compositions comprising them for selectin inhibition Download PDF

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Publication number
CN101646652A
CN101646652A CN200880010474A CN200880010474A CN101646652A CN 101646652 A CN101646652 A CN 101646652A CN 200880010474 A CN200880010474 A CN 200880010474A CN 200880010474 A CN200880010474 A CN 200880010474A CN 101646652 A CN101646652 A CN 101646652A
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formic acid
hydroxyl
quinoline
cyclopropyl
phenyl
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尼鲁·凯拉
克里斯廷·玛丽·詹兹
阿德里安·黄
亚历山德罗·法比奥·莫雷托
帕特里夏·沃德·贝达德
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Wyeth LLC
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    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

The present teachings relate to novel compounds of formula I: wherein the constituent variables are as defined herein. Compounds of the present teachings can act as antagonists of the mammalian adhesion proteins known as selectins. Methods for treating or preventing selectin-mediated disorders are provided, which include administration of these compounds in a therapeutically effective amount.

Description

The medical composition that is used to select the plain quinoline that suppresses and comprises quinoline
Technical field
The present invention relates to serve as the compounds that is called the antagonist of selecting plain Mammals attachment proteins.
Background technology
During the starting stage of vascular inflammatory, white corpuscle in the fluid flow blood and thrombocyte underspeed because of adhering to blood vessel endothelium and representing the rolling behavior.It is to combine and mediate by being called the specificity of selecting the part on plain Ca-dependent or " C type " lectin family and the leukocyte surface that this molecule is fastened incident (molecular tethering event).Also there are several disease patient's condition that can cause harmful triggering of the cell adhesion of selecting plain mediation, for example transitivity of autoimmune disorder, thrombus venereal disease disease, parasitic disease and tumour cell diffusion.
Select the short consensus repeat that is characterized as N-terminal agglutinin territory, epidermal growth factor-like territory and different numbers of the cell foreign lands of fibroin.Identified three-type-person's class and selected fibroin, comprised that palatelet-selectin (being called PADGEM or GMP-140 in the past), E-select plain (being called ELAM-1 in the past) and L-to select plain (being called LAM-1 in the past).It is to be induced on endotheliocyte via its transcription activating by pro-inflammatory cytokine to express that E-selects element.As if L-select plain constructive expression on the white corpuscle and play an important role in lymphocyte homing (lymphocyte homing).Palatelet-selectin is stored in the Weibel-Palade corpusculum of hematoblastic α particle and endotheliocyte and therefore can responds short scorching the stimulation on the surface of these cell types and expresses fast.Select plain by with leukocyte surface on the ligand molecular specificity interact and mediate adhesion.Select plain part generally to comprise the carbohydrate part at least in part.For instance, E-selects element to combine with the carbohydrate with following end structure:
Figure G2008800104747D00011
And combine with carbohydrate with following end structure:
Figure G2008800104747D00012
Wherein R is the rest part of carbohydrate chain.These carbohydrate are known blood group antigen, and (Sialyl Lewis a) to be called sialylated Louis x (Sialyl Lewis x) and sialylated Louis a usually.Sialylated Louis x antigen exists only in may be enough on the endothelial cell surface promote to select plain express cell to combine with E-.E-selects element also to combine with the carbohydrate with following end structure:
As if select element as E-, each selects plain carbohydrate combination that can be different with multiple avidity.Select the intensity of the adhesion incident (binding affinity) of plain mediation also to decide by plain density and the situation of selection on the cell surface.
The glycoprotein ligand that structure is different (comprising GlyCAM-1, CD34, ESL-1 and PSGL-1) can combine with the selection with obvious high-affinity is plain.PSGL-1 is a kind of Saliva Orthana sample homologous dimerization glycoprotein by nearly all white corpuscle Expression of Subsets, and by three kinds of each identifications of selecting in the element.Yet it is unique that PSGL-1 appears, because it is a high-affinity palatelet-selectin part main on the white corpuscle.The O-glycan that high-affinity palatelet-selectin and combining of PSGL-1 need be contained sLex and one or more sulfation tyrosine residuess be arranged in the PSGL-1 polypeptide the anion N end ( Referring toW.S. (Somers W.S.) waits people, cell (Cell), 2000,103:467-479 to Su Mosi; D. three sections (Sako D.) waits the people, cell (Cell), 1995,82 (2): 323-331; N. (Pouyani N.) waits people, cell (Cell), 1995,82 (2): 333-343 to moor inferior Buddhist nun; (Wilkins P.P.) waits people, journal of biological chemistry (J.Biol.Chem.), 1995,270 (39): 22677-22680) with the P.P. Louis Wilkins.L-selects element also to discern the N-terminal zone of PSGL-1 and has the sulfation dependency combination that is similar to palatelet-selectin to require.It is less that E-selects plain part to require to appear severity, because it can combine with the glycan that contains sLex and other glycoprotein of PSGL-1.Although palatelet-selectin gene knockout mice and P/E select plain dual gene knockout mice to show that the neutrophil content in the blood raises, these mouse still show DTH abnormal reaction and thioglycolate salt inductive peritonitis (TIP) response delay ( Referring toP.S. not raney (Frenette P.S.) waits the people, and thrombus is learned (Thromb Haemost), 1997,78 (1): 60-64) with hemostasis.The soluble form of PSGL-1 (for example rPSGL-Ig) in many animal models, shown effect ( Referring toA. (Kumar A.) waits the people, circulation (Circulation), 1999,99 (10): 1363-1369 to Ku Maer; M. (Takada M.) waits the people, Journal of Clinical Investigation (J.Clin.Invest.), 1997,99 (11): 2682-2690 in high fields; (Scalia R.) waits people, circulating research (Circ Res.), 1999,84 (1): 93-102) with the R. Antonin Scalia.
In addition, identified the gene of palatelet-selectin ligandin matter and code for said proteins. Referring toUnited States Patent (USP) the 5th, 840, No. 679.As being confirmed by palatelet-selectin/LDLR disappearance mouse, to the inhibition of palatelet-selectin represent to be applicable to treat atherosclerotic target ( Referring toR.C. Johnson (Johnson R.C.) waits the people, Journal of Clinical Investigation (J.Clin.Invest.), 1997,99:1037-1043).The expression that has been reported in atherosclerotic lesion position palatelet-selectin increases, and the value that palatelet-selectin is expressed appears relevant with lesion size.By the monocyte of palatelet-selectin mediation adhere to the very possible progress that promotes atherosclerotic plaque ( Referring toT.J.M. (Molenaar T.J.M.) waits people, biochemical pharmacology (Biochem.Pharmacol.), 2003, (66): 859-866) to Molina.
The target that also may represent to be applicable to other disease or symptom to the inhibition of palatelet-selectin, described disease or symptom comprise for example thrombosis (Wakefield people such as (Wakefield), arteriosclerosis thrombus blood vessel biology magazine (ArteriosclerThromb Vasc Biol) 28 (2008) 387-391; This people such as (Myers) of mayer, thrombus is learned (ThrombHaemost) 97 (2007) 400-407 with hemostasis), atherosclerosis thrombosis (Fu Site people such as (Fuster), american heart institute magazine (Journal of the American College of Cardiology) 46 (2005) 1209-1218), (Bean's dimension is exerted people such as (Bienvenu) to restenosis, circulation (Circulation) 103 (2001) 1128-1134), myocardial infarction (Fu Man people such as (Furman)., american heart institute magazine (Journal of the American College ofCardiology) 38 (2001) 1002-1006), ischemia-reperfusion, Raynaud's syndrome (Reynauld ' s syndrome), the inflammatory enteropathy, osteoarthritis, acute respiratory distress syndrome, asthma (Rome promise (Romano), treatment respiratory medicine (Treat Respir Med) 4 (2005) 85-94), chronic obstructive pulmonary disease (Rome promise (Romano), treatment respiratory medicine (Treat Respir Med) 4 (2005) 85-94), pulmonary emphysema, the lung inflammation, delayed hypersensitivity (Si Daite people such as (Staite), blood (Blood) 88 (1996) 2973-2979), idiopathic pulmonary fibrosis, cystic fibrosis, thermal damage, apoplexy, experimental allergic encephalomyelitis (experimental allergicencephalomyelitis), wound Secondary cases multiple organ injury syndromes, the neutrophilia tetter (the Si Weiteshi disease (Sweet ' sdisease)), glomerulonephritis (Wu Tianfu (Tianfu Wu), A﹠R (Arthritis; Rheumatism) 56 (2007) 949-959), ulcerative colitis (Irving people such as (Irving), European gastroenterology and hepatology magazine (European Journal of Gastroenterology ﹠amp; Hepatology) 20 (2008) 283-289), Crohn disease (Crohn ' s disease), necrotizing enterocolitis, the toxicity of cytokine induction, gingivitis (Coorg glug people such as (Krugluger), periodontopathy research magazine (J Periodontal Res) 28:145-151), periodontitis (Coorg glug people such as (Krugluger), periodontopathy research magazine (J Periodontal Res) 28:145-151), hemolytic uremic syndrome, psoriasis (Friedrich people such as (Friedrich), dermatological studies document (Archives ofDermatological Research) 297 (2006) 345-351), systemic lupus erythematosus, the autoimmunity thyroiditis, multiple sclerosis, rheumatoid arthritis (Ge Luobai people such as (Grober), Journal of Clinical Investigation (J.Clin.Invest.) 91 (1993) 2609-2619), Ge Leifushi disease (Grave ' s disease) (Harrar people such as (Hara), incretology magazine (Endocr J.) 43 (1996) 709-713), the immune-mediated side effect of the treatment relevant with hemodialysis or leukopheresis, the granulocyte infusion syndromes of being correlated with, venous thrombosis (this people such as (Myers) of mayer, thrombus is learned (Thromb Haemost) 97 (2007) 400-407 with hemostasis), syndromes behind the thrombosis, unstable angina, transient ischemic attack, periphery vascular disease (for example peripheral arterial disease) (Fan Deqi people such as (van der Zee), clinical chemistry (Clin Chem) 52 (2006) 657-664), the transfer relevant (Mai Kaiweier (McEver) with cancer, glycoconjugate magazine (Glycoconjugate Journal) 14 (1997) 585-591), sickle cell's syndromes (including, but is not limited to sicklemia) (Blanc people such as (Blann), thrombosis and thrombolysis magazine (Journal ofThrombosis and Thrombolysis), 10.1007/s11239-007-0177-7 (on December 14th, 2007)), organ rejection response (graft versus host) or congestive heart failure.
Known selection is plain works in many important bioprocesss (comprising inflammation and adhesion process), the visible plain inhibitor of new selection that constantly needs.
Summary of the invention
The invention provides formula I compound:
Figure G2008800104747D00041
With its pharmaceutically acceptable salt, hydrate and ester, wherein R 1, R 2, R 3, R 3', R 4, R 5, R 6, R 7, R 8With n as defined herein.
The invention still further relates to medical composition, it comprises one or more formulas I compound (or its pharmaceutically acceptable salt, hydrate or ester) and the pharmaceutically acceptable supporting agent or the vehicle of medical significant quantity.The present invention also provides the method for preparation and the formula of use I compound and its pharmaceutically acceptable salt, hydrate and ester.In certain embodiments, the invention provides treatment and suffer from the mammiferous method of the symptom that is characterized as the intercellular adhesion process of selecting plain mediation, for example by regulating adhesion in the cell of selecting plain mediation in the mammalian body at least in part to described Mammals throwing and one or more formulas I compound (or its pharmaceutically acceptable salt, hydrate and ester) of significant quantity.
Description of drawings
Do not have
Embodiment
The invention provides formula I compound:
Figure G2008800104747D00051
With its pharmaceutically acceptable salt, hydrate and ester, wherein:
R 1For-OR 9,-C (O) R 10,-C (O) OR 9,-C (O) NR 10R 11,-C (S) R 10,-C (S) OR 9,-C (S) NR 10R 11,-C (NR 10) R 10,-C (NR 10) NR 10R 11,-NR 10R 11,-NR 11C (O) R 10,-NR 11C (O) NR 10R 11,-NR 11C (NR 10) NR 10R 11,-NR 11S (O) mR 10Or-NR 11S (O) mNR 10R 11
R 2For-C (O) OR 9,-C (O) NR 10R 11Or carboxylic acid bioisostere;
R 3And R 3' be independently H ,-CN ,-NO 2, halogen ,-OR 9,-NR 10R 11,-S (O) mR 10,-S (O) mOR 9,-S (O) mNR 10R 11,-C (O) R 10,-C (O) OR 9,-C (O) NR 10R 11,-C (S) R 10,-C (S) OR 9,-C (S) NR 10R 11,-C (NR 10) NR 10R 11, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces; Or
Perhaps, R 3And R 3' can form C together with the carbon atom that is connected separately 4-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 4-14 unit ring or 5-14 unit heteroaryl, wherein said C 4-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 4-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 4And R 5Be H, C independently 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces; Or
Perhaps, R 4And R 5Form C together with its corresponding shared carbon atom 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 6And R 7When occurring, be H, C independently at every turn 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces; Or
Perhaps, R 6And R 7Can form C together with its corresponding shared carbon atom 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
Condition is R 4And R 5With R 6And R 7In at least one form C together with its corresponding shared carbon atom 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 8Be C 6-14Aryl or 5-14 unit heteroaryl, wherein said C 6-14Aryl and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 9When occurring at every turn independently for H ,-C (O) R 10,-C (O) NR 10R 11,-C (S) R 10,-C (S) NR 10R 11,-C (NR 10) R 10,-C (NR 10) NR 10R 11,-S (O) mR 10,-S (O) mNR 10R 11, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 10And R 11When occurring at every turn independently for H ,-OH ,-SH ,-S (O) 2OH ,-C (O) OH ,-C (O) NH 2,-C (S) NH 2,-OC 1-10Alkyl ,-C (O)-C 1-10Alkyl ,-C (O)-OC 1-10Alkyl ,-OC 6-14Aryl ,-C (O)-C 6-14Aryl ,-C (O)-OC 6-14Aryl ,-C (S) N (C 1-10Alkyl) 2,-C (S) NH-C 1-10Alkyl ,-C (O) NH-C 1-10Alkyl ,-C (O) N (C 1-10Alkyl) 2,-C (O) NH-C 6-14Aryl ,-S (O) m-C 1-10Alkyl ,-S (O) m-OC 1-10Alkyl, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 12When occurring at every turn independently for halogen ,-CN ,-NO 2, oxo ,-O-Z-R 13,-NR 13-Z-R 14,-N (O) R 13-Z-R 14,-S (O) mR 13,-S (O) mO-Z-R 13,-S (O) mNR 13-Z-R 14,-C (O) R 13,-C (O) O-Z-R 13,-C (O) NR 13-Z-R 14,-C (S) NR 13-Z-R 14,-Si (C 1-10Alkyl) 3, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 15Group replaces;
R 13And R 14When occurring at every turn independently for H ,-OH ,-SH ,-S (O) 2OH ,-C (O) OH ,-C (O) NH 2,-C (S) NH 2,-OC 1-10Alkyl ,-C (O)-C 1-10Alkyl ,-C (O)-OC 1-10Alkyl ,-C (S) N (C 1-10Alkyl) 2,-C (S) NH-C 1-10Alkyl ,-C (O) NH-C 1-10Alkyl ,-C (O) N (C 1-10Alkyl) 2,-S (O) m-C 1-10Alkyl ,-S (O) m-OC 1-10Alkyl, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 15Group replaces;
R 15When occurring at every turn independently for halogen ,-CN ,-NO 2, oxo ,-OH ,-NH 2,-NH (C 1-10Alkyl) ,-N (C 1-10Alkyl) 2,-S (O) mH ,-S (O) m-C 1-10Alkyl ,-S (O) 2OH, 1)-S (O) m-OC 1-10Alkyl ,-CHO ,-C (O)-C 1-10Alkyl ,-C (O) OH ,-C (O)-OC 1-10Alkyl ,-C (O) NH 2,-C (O) NH-C 1-10Alkyl ,-C (O) N (C 1-10Alkyl) 2,-C (S) NH 2,-C (S) NH-C 1-10Alkyl ,-C (S) N (C 1-10Alkyl) 2,-S (O) mNH 2,-S (O) mNH (C 1-10Alkyl) ,-S (O) mN (C 1-10Alkyl) 2,-Si (C 1-10Alkyl) 3, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 1-10Alkoxyl group, C 1-10Alkylhalide group, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl;
Z is divalence C at every turn independently when occurring 1-10Alkyl, divalence C 2-10Thiazolinyl, divalence C 2-10Alkynyl, divalence C 1-10Alkylhalide group or covalent linkage;
M is 0,1 or 2 when occurring at every turn independently; And
N is 0,1 or 2.
In certain embodiments, R 1Can be-OR 9Or-NR 10R 11, R wherein 9Can be H ,-C (O) R 10,-C (O) NR 10R 11,-C (S) R 10,-C (S) NR 10R 11,-S (O) mR 10,-S (O) mNR 10R 11, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl respectively can be randomly through 1-4-Z-R 12Group replaces, and R 10, R 11, R 12, Z and m as defined herein.For instance, R 1Can be-OH ,-OC (O) R 10,-OC (O) NR 10R 11,-OS (O) mR 10,-OS (O) mNR 10R 11Or-NR 10R 11In certain embodiments, R 1Can be-OH ,-OC (O) R 10Or-NR 10R 11In a particular embodiment, R 1Can be-OH.
In certain embodiments, R 2Can be-C (O) OR 9, R wherein 9As defined herein.In certain embodiments, R 9Can be H, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Assorted alkyl of aryl, described 3-14 unit ring and described 5-14 unit heteroaryl each independently and randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.For instance, R 2Can be-C (O) OH.
In other embodiments, R 2Can be-C (O) NR 10R 11, R wherein 10And R 11As defined herein.For instance, R 10And R 11Can be H, C independently 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces.In a particular embodiment, R 2Can be-C (O) NH 2Or-C (O) NHR 10, R wherein 10Can be C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces.
In other embodiments, R 2Can be the carboxylic acid bioisostere, for example (but being not limited to) acid amides, sulphonamide, sulfonic acid, 3-hydroxyl-4H-pyrans-4-ketone, imidazoles, oxazole, thiazole, pyrazoles, triazole, oxadiazole, thiadiazoles or tetrazolium respectively can randomly be substituted (for example through C 1-10Replacement such as alkyl, OH).
In certain embodiments, compound of the present invention can be represented by formula Ia, formula Ib, formula Ic, formula Id, formula Ie or formula If:
Figure G2008800104747D00091
R wherein 1, R 2, R 3, R 3', R 4, R 5, R 6, R 7, R 8With n as defined herein.
In some embodiment of the compound of representing by formula I, formula Ia, formula Ib, formula Ic, formula Id, formula Ie or formula If, R 3And R 3' can be independently H, halogen ,-OR 9,-C (O) OR 9, C 1-10Alkyl, C 3-14Cycloalkyl, C 6-14Aryl or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 3-14Cycloalkyl, described C 6-14Aryl and described 5-14 unit heteroaryl respectively can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.In certain embodiments, R 3And R 3' can be independently H, F, Cl, Br ,-OH ,-O (C 1-6Alkyl) ,-COOH, C 1-6Alkyl, C 3-10Cycloalkyl, phenyl or 5-10 unit heteroaryl, wherein said C 1-6Alkyl, described C 3-10Cycloalkyl, described phenyl and described 5-10 unit heteroaryl respectively can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.For instance, R 3And R 3' can be independently-O-(C 1-6Alkyl), wherein said C 1-6Alkyl can randomly be substituted (for example ,-OCH 3,-OCH 2CH 3,-OCH (CH 3) 2,-OCH 2CH 2CH 3,-OC (CH 3) 3With-OCF 3), can be the straight or branched C that randomly is substituted 1-6Alkyl (for example, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl ,-CF 3,-C (CH 3) 2OH ,-C (CF 3) (CH 3) OH and-C (CF 3) 2OH) or the C that randomly is substituted 3-14Cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl).In certain embodiments, R 3And R 3' can be independently H ,-C (CH 3) 2OH ,-C (CF 3) (CH 3) OH or-C (CF 3) 2OH.In certain embodiments, R 3Can be H and R 3' can be-C (CF 3) 2OH.In other embodiments, R 3Can be-C (CF 3) 2OH and R 3' can be H.In other embodiments, R 3And R 3' can be H simultaneously.In certain embodiments, R 3Or R 3' can be phenyl or thienyl, each can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.
In other embodiments, R 3And R 3' can form C together with the carbon atom that is connected separately 4-14Cycloalkyl or the assorted alkyl of 4-14 unit ring, wherein said C 4-14Cycloalkyl and the assorted alkyl of described 4-14 unit ring respectively can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.The example of cycloalkyl and the assorted alkyl of ring includes, but is not limited to cyclohexyl and piperidyl, and each can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.For instance, R 3And R 3' can form cyclohexyl together with the carbon atom that it connected.In certain embodiments, compound of the present invention has formula Ig:
Figure G2008800104747D00101
R wherein 1, R 2, R 4, R 5, R 6, R 7, R 8With n as defined herein.
In certain embodiments, R 4And R 5Can be H or independently randomly through 1-4-Z-R 12The C that group replaces 1-6Alkyl, wherein Z and R 12As defined herein.In other embodiments, R 4And R 5Can form C together with its shared carbon atom 3-14Cycloalkyl or the assorted alkyl of 3-14 unit ring, wherein said C 3-14Cycloalkyl and the assorted alkyl of described 3-14 unit ring respectively can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.In certain embodiments, R 4And R 5Can form randomly through 1-4-Z-R together with its shared carbon atom 12The C that group replaces 3-14Alkyl, and Z and R 12As defined herein.C 3-14The example of cycloalkyl includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, and each can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.In a particular embodiment, R 4And R 5Can form cyclopropyl or cyclobutyl together with its shared carbon atom.
In certain embodiments, R 6And R 7When occurring, can be H or C independently at every turn 1-6Alkyl, wherein said C 1-6Alkyl can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.In other embodiments, R 6And R 7Can form C together with its shared carbon atom 3-14Cycloalkyl or the assorted alkyl of 3-14 unit ring, the assorted alkyl of described cycloalkyl or described ring respectively can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.For instance, C 3-14Cycloalkyl can be cyclopropyl.
In certain embodiments, R 4And R 5With R 6And R 7In at least one can form C together with its corresponding shared carbon atom 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.In certain embodiments, work as R 4And R 5Form C 3-14Cycloalkyl and n are 1 o'clock, R 6And R 7Can be H or independently randomly through 1-4-Z-R 12The C that group replaces 1-6Alkyl, wherein Z and R 12As defined herein.In other embodiments, work as R 4And R 5Can be H or independently randomly through 1-4-Z-R 12The C that group replaces 1-6Alkyl and n are 1 o'clock, R 6And R 7Can form C 3-14Cycloalkyl, wherein Z and R 12As defined herein.
In certain embodiments, R 8Can be randomly through 1-4-Z-R 12The C that group replaces 6-14Aryl, and Z and R 12As defined herein.In certain embodiments, R 8Can be randomly through halogen ,-O-Z-R 13, C 1-10Alkyl or C 1-10The C that alkylhalide group replaces 6-14Aryl, wherein Z and R 13As defined herein.For instance, R 8Can be randomly through F, Cl, Br ,-OCH 3,-CH 3,-CF 3With-OCF 3The phenyl that replaces.
In certain embodiments, R 8Can be randomly through 1-4-Z-R 12The 5-14 unit heteroaryl that group replaces, and Z and R 12As defined herein.In certain embodiments, R 8Can be randomly through 1-4-Z-R 12The thienyl that group replaces, and Z and R 12As defined herein.In a particular embodiment, R 8Can be the thienyl that is unsubstituted.
In some embodiment of compound of the present invention, n can be 0.In other embodiments, n can be 1.
For n is 0 embodiment, and compound of the present invention can be represented by formula II:
Figure G2008800104747D00121
R wherein 1, R 2, R 3, R 3', R 4, R 5And R 8As defined herein.Some compound of these embodiment can further be represented by formula IIa, formula IIb, formula IIc, formula IId, formula IIe or formula IIf:
Figure G2008800104747D00122
Figure G2008800104747D00131
R wherein 1, R 2, R 3, R 3', R 4, R 5And R 8As defined herein.
In some embodiment of the compound of representing by formula II, formula IIa, formula IIb, formula IIc, formula IId, formula IIe or formula IIf, R 3And R 3' form C together with the carbon atom that is connected separately 4-14Cycloalkyl or the assorted alkyl of 4-14 unit ring, wherein said C 4-14Cycloalkyl and the assorted alkyl of described 4-14 unit ring are respectively randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.In certain embodiments, R 3And R 3' form C together with the carbon atom that is connected separately 6Cycloalkyl.For instance, compound of the present invention can have the structure of formula IIg:
Figure G2008800104747D00132
R wherein 1, R 2, R 4, R 5And R 8As defined herein.
In some embodiment of the compound of representing by formula II, formula IIa, formula IIb, formula IIc, formula IId, formula IIe, formula IIf or formula IIg, R 4And R 5Can form C together with its shared carbon atom 3-14Cycloalkyl or the assorted alkyl of 3-14 unit ring, wherein said C 3-14Cycloalkyl and the assorted alkyl of described 3-14 unit ring respectively can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.In certain embodiments, R 4And R 5Can form randomly through 1-4-Z-R together with its shared carbon atom 12The C that group replaces 3-14Alkyl, and Z and R 12As defined herein.C 3-14The example of cycloalkyl includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, and each can be randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.In a particular embodiment, R 4And R 5Can form cyclopropyl or cyclobutyl together with its shared carbon atom.
In some embodiment of compound of the present invention, R 2The compound that can be C (O) OH and these embodiment can be represented by formula III, formula III a or formula III b:
Figure G2008800104747D00141
R wherein 1, R 3, R 3', R 4, R 5, R 6, R 7, R 8With n as defined herein.In certain embodiments, n can be 0, and the compound of these embodiment can further be represented by formula IV, formula IVa or formula IVb:
Figure G2008800104747D00151
R wherein 1, R 3, R 3', R 4, R 5And R 8As defined herein.
In some embodiment of the compound of representing by formula III, formula III a, formula III b, formula IV, formula IVa or formula IVb, R 3And R 3' form C together with the carbon atom that is connected separately 4-14Cycloalkyl or the assorted alkyl of 4-14 unit ring, wherein said C 4-14Cycloalkyl and the assorted alkyl of described 4-14 unit ring are respectively randomly through 1-4-Z-R 12Group replaces, and Z and R 12As defined herein.In certain embodiments, R 3And R 3' form C together with the carbon atom that is connected separately 6Cycloalkyl.For instance, compound of the present invention can have the structure of formula III c or IVc:
Figure G2008800104747D00161
R wherein 1, R 4, R 5, R 6, R 7, R 8With n as defined herein.
Run through composition is described as having, comprises or comprises specific components, or technology is described as having, comprising or comprise the description of specific process step, expect that composition of the present invention also is made up of described component basically or is made up of described component, and technology of the present invention is made up of described procedure of processing basically also or is made up of described procedure of processing.
In the application's case, when think element or component be included in the inventory of the element of stating or component and/or when being selected from described inventory, should be appreciated that described element or component can be any and the optional freedom in the element of stating or the component two or more the group that forms of the element of stating or component.
Unless special stipulation in addition, otherwise the use of singulative herein comprises plural form (and the use of plural form also comprises singulative).In addition, when before numerical value, using term " about ", unless special stipulation in addition, the present invention also comprises special value itself.
Should be appreciated that the order of step or to carry out the order of some action unimportant is as long as the present invention is still practical.In addition, two or more steps or action can be carried out simultaneously.
As used herein, " halogen " or " halogen " is meant fluorine-based, chloro, bromo and iodo.
As used herein, " oxo " is meant that double-bond-ed oxygen (that is ,=O).
As used herein, " alkyl " is meant the straight or branched saturated hydrocarbyl.The example of alkyl comprises methyl (Me), ethyl (Et), propyl group (for example, n-propyl and sec.-propyl), butyl (for example, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl), amyl group (for example, n-pentyl, isopentyl, neo-pentyl) etc.In certain embodiments, alkyl can be independently selected from-Z-R through reaching four 12Group and-Z-R 15The substituting group of group replaces, wherein Z, R 12And R 15As described herein.Low-carbon alkyl has nearly 6 carbon atoms usually.The example of low-carbon alkyl comprises methyl, ethyl, propyl group (for example, n-propyl and sec.-propyl) and butyl (for example, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl).
As used herein, " thiazolinyl " is meant the straight or branched alkyl with one or more carbon-to-carbon double bonds.The example of thiazolinyl includes, but is not limited to vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl etc.Described one or more carbon-to-carbon double bonds can be positioned at inside (for example 2-butylene) or terminal (for example 1-butylene).In certain embodiments, thiazolinyl can be independently selected from-Z-R through reaching four 12Group and-Z-R 15The substituting group of group replaces, wherein Z, R 12And R 15As described herein.
As used herein, " alkynyl " is meant the straight or branched alkyl with one or more carbon-to-carbon triple bonds.The example of alkynyl includes, but is not limited to ethynyl, proyl, butynyl, pentynyl etc.Described one or more carbon-to-carbon triple bonds can be positioned at inside (for example 2-butyne) or terminal (for example ethyl acetylene).In certain embodiments, alkynyl can be independently selected from-Z-R through reaching four 12Group and-Z-R 15The substituting group of group replaces, wherein Z, R 12And R 15As described herein.
As used herein, " alkoxyl group " is meant-the O-alkyl.The example of alkoxyl group includes, but is not limited to methoxyl group, oxyethyl group, propoxy-(for example, positive propoxy and isopropoxy), tert.-butoxy etc.In certain embodiments ,-alkyl in the O-alkyl can through nearly four be independently selected from-Z-R 12Group and-Z-R 15The substituting group of group replaces, wherein Z, R 12And R 15As described herein.
As used herein, " alkylthio " is meant-the S-alkyl.The example of alkylthio includes, but is not limited to methylthio group, ethylmercapto group, rosickyite base (for example, positive rosickyite base and iprotiazem base), uncle's butylthio etc.In certain embodiments ,-alkyl in the S-alkyl can through nearly four be independently selected from-Z-R 12Group and-Z-R 15The substituting group of group replaces, wherein Z, R 12And R 15As described herein.
As used herein, " alkylhalide group " is meant the alkyl with one or more halogenic substituents.The example of alkylhalide group includes, but is not limited to CF 3, C 2F 5, CHF 2, CH 2F, CCl 3, CHCl 2, CH 2Cl, C 2Cl 5Deng.Comprise perhaloalkyl radical in the definition of " alkylhalide group ", promptly all hydrogen atoms are all by halogen atom metathetical alkyl (for example, CF 3And C 2F 5).
As used herein, " cycloalkyl " is meant the non-aromatic carbocylic radical, comprises cyclisation alkyl, thiazolinyl and alkynyl, for example has 3 to 14 ring carbon atoms and randomly contains one or more (for example, 1,2 or 3) two keys or triple bonds.Cycloalkyl can be monocyclic groups (for example, cyclohexyl) or many cyclic groups (for example, containing condensed ring, bridged ring and/or volution system), and wherein carbon atom is positioned at the inside or the outside of described loop systems.Any suitable ring position of cycloalkyl all can be covalently bound with the chemical structure that limits.The example of cycloalkyl includes, but is not limited to cyclopropyl, cyclopropyl methyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl methyl, cyclohexyl ethyl, suberyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatriene base, norcamphyl, falls pinane base, norcaryl, adamantyl and spiral shell [4.5] decyl, with and homologue, isomer etc.In certain embodiments, cycloalkyl can be independently selected from-Z-R through reaching four 12Group and-Z-R 15The substituting group of group replaces, wherein Z, R 12And R 15As described herein.In certain embodiments, cycloalkyl can replace through one or more oxo bases.
As used herein, " heteroatoms " is meant beyond de-carbon or the hydrogen any atoms of elements and comprises for example nitrogen (N), oxygen (O), sulphur (S), phosphorus (P) and selenium (Se).
As used herein, " the assorted alkyl of ring " is meant the non-aromatic cycloalkyl with 3-24 annular atoms, it contains at least one (for example, 1-5) and is selected from the ring hetero atom of O, N and S and randomly contains one or more (for example, 1,2 or 3) two keys or triple bonds.The assorted alkyl of ring can connect the chemical structure that limits at any heteroatoms or carbon atom place, thereby produces stable structure.One or more N or S atom in the assorted alkyl ring of ring can be through oxidation (for example, morpholine N-oxide compound, thiomorpholine S-oxide compound, thiomorpholine S, S-dioxide).In certain embodiments, the nitrogen-atoms of the assorted alkyl of ring can have substituting group, for example-and Z-R 12Group and-Z-R 15Group, wherein Z, R 12And R 15As described herein.The assorted alkyl of ring also can contain one or more oxo bases, for example phthalic imidine, piperidone, oxazolidone, pyrimidine-2,4 (1H, 3H)-diketone, pyridine-2 (1H)-ketone etc.The example of the assorted alkyl of ring comprises morpholine, thiomorpholine, pyrans, imidazolidine, tetrahydroglyoxaline, oxazolidine, pyrazolidine, pyrazoline, tetramethyleneimine, pyrroline, tetrahydrofuran (THF), tetramethylene sulfide, piperidines, piperazine etc.In certain embodiments, the assorted alkyl of ring can randomly be independently selected from-Z-R through reaching four 12Group and-Z-R 15The substituting group of group replaces, wherein Z, R 12And R 15As described herein.
As used herein, " aryl " is meant aromatic series monocyclic hydrocarbon loop systems, or by aromatic series monocyclic hydrocarbon ring and at least one other aromatic hydrocarbons ring and/or non-aromatic carbocyclic ring or the heterocyclic fused multi-loop system that forms.In certain embodiments, monocyclic aryl can have 6 to 14 carbon atoms and polyaromatic can have 8 to 14 carbon atoms.Any suitable ring position of aryl all can be covalently bound with the chemical structure that limits.In certain embodiments, aryl can only have aromatic carbon ring, for example phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl etc.In other embodiments, aryl can be the multi-loop system that the assorted alkyl ring of at least one aromatic carbon ring and one or more cycloalkyl or ring condenses (that is, having shared key).The example of described aryl comprises that the benzo derivative of pentamethylene (is the dihydro indenyl, it is 5,6-bicyclic cycloalkyl/aromatic nucleus system), the benzo derivative of hexanaphthene (is a tetralyl, it is 6,6-bicyclic cycloalkyl/aromatic nucleus system), the benzo derivative of tetrahydroglyoxaline (be the benzimidazoline base, it is 5,6-dicyclo ring mix alkyl/aromatic nucleus system) and the benzo derivative of pyrans (are benzopyranyl, it is 6, the 6-dicyclo ring alkyl/aromatic nucleus system that mixes).Other example of aryl includes, but is not limited to benzodioxan base, benzo dioxolyl, chromanyl, indoline base etc.In certain embodiments, aryl can randomly contain nearly four and is independently selected from-Z-R 12Group and-Z-R 15The substituting group of group, wherein Z, R 12And R 15As described herein.
As used herein, " heteroaryl " is meant and contains at least 1 aromatic series single-loop system that is selected from the ring hetero atom of oxygen (O), nitrogen (N) and sulphur (S), or at least one ring that exists in the loop systems is aromatic nucleus and the multi-loop system that contains at least 1 ring hetero atom.Generally speaking, heteroaryl for example can have 5 to 14 annular atomses and contain 1-5 ring hetero atom.Heteroaryl comprises and the assorted alkyl ring condensed bicyclic heteroaryl ring of one or more aromatic carbon rings, non-aromatic carbocyclic ring and non-aromatic ring.Described heteroaryl can connect the chemical structure that limits at any heteroatoms or carbon atom place, thereby produces stable structure.Heteroaryl ring does not generally contain O-O, S-S or S-O key.Yet one or more N in the heteroaryl or S atom can be through oxidation (for example, pyridine N-oxides, thiophene S-oxide compound, thiophene S, S-dioxide).5 yuan of single-loop systems shown in the example of heteroaryl for example comprises hereinafter and 5-6 bicyclic system:
Wherein T is O, S, NH, N-Z-R 12Or N-Z-R 15, and Z, R 12And R 15The as described herein definition.The example of described heteroaryl ring includes, but is not limited to pyrryl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl group isoxazolyl oxazolyl oxadiazole base, indyl, pseudoindoyl, benzofuryl, benzothienyl, quinolyl, 2-toluquinoline base, isoquinolyl, quinoxalinyl, quinazolyl, the benzotriazole base, benzimidazolyl-, benzothiazolyl, the benzisothiazole base, benzoisoxazole base Ben Bing oxadiazole base benzoxazolyl, the cinnolines base, the 1H-indazolyl, the 2H-indazolyl, the indolizine base, isobenzofuran-base, naphthyridinyl, phthalazinyl, pteridyl, purine radicals oxazole and pyridyl, thiazole and pyridyl, imidazopyridyl, the furo pyridyl, the thienopyridine base, the Pyridopyrimidine base, the pyrido-pyrazine base, the pyrido pyridazinyl, the thieno-thiazolyl, thiophene Bing oxazolyl, Thienoimidazole base etc.Other example of heteroaryl includes, but is not limited to 4,5,6,7-tetrahydro indole base, tetrahydric quinoline group, thionaphthene and pyridyl, cumarone and pyridyl etc.In certain embodiments, heteroaryl can be independently selected from-Z-R through reaching four 12Group and-Z-R 15The substituting group of group replaces, wherein Z, R 12And R 15As described herein.
As used herein, " carboxylic acid bioisostere " is meant chemistry with the carboxylic moiety of being similar to or physical properties and produces the substituting group or the group of the biological property that roughly is similar to carboxylic moiety. Generally referring to, R.B. Gary Silverman (R.B.Silverman), the organic chemistry of medicinal design and medicine behavior (The Organic Chemistry of DrugDesign and Drug Action) (academic press (Academic Press), 1992).The example of carboxylic acid bioisostere includes, but is not limited to acid amides, sulphonamide, sulfonic acid, phosphonamidic acid (phosphonamidic acid), phosphonic acids alkane ester, N-malonamide nitrile, 3-hydroxyl-4H-pyrans-4-ketone, imidazoles, oxazole, thiazole, pyrazoles, triazole, oxadiazole, thiadiazoles or tetrazolium, each can randomly be substituted (for example, through C 1-10Replacement such as alkyl, OH).Other example of carboxylic acid bioisostere can include, but is not limited to-OH and hereinafter shown in each thing:
Figure G2008800104747D00201
R wherein 3, R 9And R 10As defined herein.
Compound of the present invention can comprise and is defined as " divalent group " that can form the linking group of covalent linkage with two other parts herein.For instance, compound as herein described can comprise divalence C 1-10Alkyl, for example methylene radical.
Place, many places in this manual, the substituting group of compound are the form announcements with group or scope.Plan particularly, describe content and comprise that each discrete subgroup of the member of described group and scope closes.For instance, term " C 1-10Alkyl " plan individually to disclose C particularly 1, C 2, C 3, C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 1-C 10, C 1-C 9, C 1-C 8, C 1-C 7, C 1-C 6, C 1-C 5, C 1-C 4, C 1-C 3, C 1-C 2, C 2-C 10, C 2-C 9, C 2-C 8, C 2-C 7, C 2-C 6, C 2-C 5, C 2-C 4, C 2-C 3, C 3-C 10, C 3-C 9, C 3-C 8, C 3-C 7, C 3-C 6, C 3-C 5, C 3-C 4, C 4-C 10, C 4-C 9, C 4-C 8, C 4-C 7, C 4-C 6, C 4-C 5, C 5-C 10, C 5-C 9, C 5-C 8, C 5-C 7, C 5-C 6, C 6-C 10, C 6-C 9, C 6-C 8, C 6-C 7, C 7-C 10, C 7-C 9, C 7-C 8, C 8-C 10, C 8-C 9And C 9-C 10Alkyl.Other lifts an example, and term " 5-14 unit heteroaryl " plan particularly individually discloses and has 5,6,7,8,9,10,11,12,13,14,5-14,5-13,5-12,5-11,5-10,5-9,5-8,5-7,5-6,6-14,6-13,6-12,6-11,6-10,6-9,6-8,6-7,7-14,7-13,7-12,7-11,7-10,7-9,7-8,8-14,8-13,8-12,8-11,8-10,8-9,9-14,9-13,9-12,9-11,9-10,10-14,10-13,10-12,10-11,11-14,11-13,11-12,12-14, the heteroaryl of a 12-13 or 13-14 annular atoms.
Compound as herein described can contain asymmetric atom (being called chiral centre again), and some compounds can contain one or more asymmetric atoms or center, can produce optical isomer (enantiomer) and diastereomer thus.Present invention disclosed herein and compound comprise described optical isomer (enantiomer) and diastereomer (geometrical isomer), and the R of the enantiomer-pure of racemize and fractionation and S steric isomer, and other mixture of R and S steric isomer and its pharmaceutically acceptable salt.Optical isomer can obtain with pure form by the known standard program of those skilled in the art, and described program comprises (but being not limited to) diastereoisomerism salt formation, kinetic resolution and asymmetric synthesis.The cis and the trans-isomer(ide) of the compound (for example, alkene and imines) that contains alkenyl part also contained in the present invention.Should also be clear that, all possible positional isomers and its mixture are contained in the present invention, it can obtain with pure form by the known standard separable programming of those skilled in the art, and described program comprises (but being not limited to) column chromatography, tlc and high efficiency liquid chromatography.
Run through whole specification sheets, structure may present or may not present with chemical name with chemical name.When any problem of occurring about nomenclature, structure is the most convincing.
The present invention also provides the prodrug of compound disclosed herein.As used herein, " prodrug " be meant when throw to mammalian subject with the time can produce, generate or discharge the part of compound of the present invention.Can utilize parent compound by preparing prodrug with existing functional group in the ad hoc fashion modified compound, described mode makes can pass through routine operation or the described modification of cracking in vivo.The example of prodrug comprises compound as described herein, it contains one or more molecular moieties on hydroxyl, amino, thiohydroxy or the carboxyl that is attached to described compound, and when throw to mammalian subject and the time, its can cracking in vivo to form free hydroxyl group, amino, thiohydroxy or carboxyl respectively.The example of prodrug can include, but is not limited to acetic ester, manthanoate and the benzoate derivatives of the alkohol and amine functional group in the compound of the present invention.The preparation of prodrug and use are at Gutter mouth T. (T.Higuchi) and Si Tela V. (V.Stella), " as the prodrug (Pro-drugs as Novel Delivery Systems) of novel transfer system; " A.C.S. the 14th of discussion series (A.C.S.Symposium Series) the roll up, with the biological reversible supporting agent (Bioreversible Carriers inDrug Design) in the medicinal design, Edward B. Luo Qi (Edward B.Roche) compiles, American Pharmaceutical Association and Pei Geman press (American Pharmaceutical Association and Pergamon Press), discussed in 1987, the whole disclosure of described document is incorporated herein by reference for all purposes.
Known pharmaceutically acceptable ester in the field under the ester-formin of compound of the present invention comprises, it can be a free acid form at the Mammals internal metabolism, for example free carboxy acid's form.The example of suitable ester (for example includes, but is not limited to the alkane ester, the alkyl of 1 to 10 carbon atom), the cycloalkanes ester (for example, 3-10 carbon atom), aromatic ester (for example, 6-14 carbon atom, comprise 6-10 carbon atom) and its heterocyclic analogs is (for example, 3-14 annular atoms, wherein 1-3 can be selected from oxygen, nitrogen and sulfur heteroatom), and pure residue can have other substituting group.In certain embodiments, the ester of compound disclosed herein can be C 1-10Alkane ester, for example methyl esters, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, the tert-butyl ester, pentyl ester, isopentyl ester, peopentyl ester and own ester; C 3-10The cycloalkanes ester for example encircles propyl ester, cyclopropyl methyl esters, ring butyl ester, ring pentyl ester and cyclohexyl; Or aromatic ester, for example phenyl ester, benzene methyl and toluene ester.
The pharmaceutically acceptable salt of the had acidic moiety of The compounds of this invention can use organic bases and mineral alkali to form.Number on the acidic hydrogen that can be used for deprotonation is decided, expection single anion salt and polyanionic salt.The suitable salt that forms with alkali comprises metal-salt, for example basic metal or alkaline earth salt, for example sodium salt, sylvite or magnesium salts; Ammonia salt and organic amine salt, for example with morpholine, thiomorpholine, piperidines, tetramethyleneimine, single low-carbon alkyl amine, two low-carbon alkyl amine or three low-carbon alkyl amine (for example, ethyl-TERTIARY BUTYL AMINE, diethylamine, Diisopropylamine, triethylamine, Tributylamine or dimethyl propylamine) or the salt that forms of monohydroxy low-carbon alkyl amine, dihydroxyl low-carbon alkyl amine or trihydroxy-low-carbon alkyl amine (for example, monoethanolamine, diethanolamine or trolamine).The specific limiting examples of mineral alkali comprises NaHCO 3, Na 2CO 3, KHCO 3, K 2CO 3, Cs 2CO 3, LiOH, NaOH, KOH, NaH 2PO 4, Na 2HPO 4And Na 3PO 4Also can form inner salt.Similarly, when compound disclosed herein contains basic moiety, can use organic acid and mineral acid to form salt.For instance, can form salt by following acid: acetate, propionic acid, lactic acid, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, tartrate, succsinic acid, dichloro acetic acid, vinyl sulfonic acid, formic acid, fumaric acid, glyconic acid, L-glutamic acid, urobenzoic acid, Hydrogen bromide, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, methanesulfonic, glactaric acid, naphthene sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, succsinic acid, sulfuric acid, tartrate, toluenesulphonic acids and camphorsulfonic acid and other known pharmaceutically acceptable acid.
The present invention also provides the medical composition that comprises at least a compound as herein described and one or more pharmaceutically acceptable supporting agents, vehicle or thinner.The example of described supporting agent is known by the those skilled in the art and can be prepared according to acceptable medical program, Lei Mingdengshi pharmacy science (Remington ' s PharmaceuticalSciences) for example, the 17th edition, A Erfunuosuo R. Ge Naluo (Alfonoso R.Gennaro) compiles, mark press (MackPublishing Company), Pennsylvania Easton (Easton, PA) program described in (1985), the whole disclosure of described document is incorporated herein by reference for all purposes.As used herein, " pharmaceutically acceptable " be meant from the toxicology viewpoint tolerable be used for medical applications and not can with the interactional unfriendly material of activeconstituents.Therefore, pharmaceutically acceptable supporting agent be with composite in the compatible supporting agent of other composition and be biologically acceptable.The complementarity activeconstituents also can be incorporated in the medical composition.
Compound of the present invention can be oral or intestines outer with pure form throw with or with the medical supporting agent combination of routine throw with.The solid carriers that is suitable for can comprise that one or more also can serve as the material of seasonings, lubricant, solubilizing agent, suspension agent, weighting agent, glidant, compression aid, tackiness agent or tablet disintegrant or capsule envelope material.Described compound can for example be allocated to be similar to the mode that is used for known antiphlogistic in a usual manner.The oral composite that contains compound disclosed herein can comprise any oral form commonly used, comprises tablet, capsule, cheek form, lozenge (troche), sucks ingot (lozenge) and liquid oral, suspension or solution.Under the powder situation, supporting agent can be the finely powdered solid, and it is the mixture with the finely powdered compound formation.Under the tablet situation, can make compound disclosed herein and have the supporting agent of essential compression property with suitable mixed and with desired shape and size compacting.Described powder and tablet can contain nearly 99% described compound.
Capsule can contain the mixture of one or more compounds disclosed herein and inert filler and/or thinner, the for example pharmaceutically acceptable starch of described inert filler and/or thinner (for example, corn, potato or tapioca (flour)), carbohydrate, artificial sweetner, powdery cellulose (for example, crystallization and Microcrystalline Cellulose), flour, gelatin, natural gum etc.
The tablet formulations that is suitable for can be by conventional compression; wet granulation or dry type granulating method prepare and utilize pharmaceutically acceptable thinner; tackiness agent; lubricant; disintegrating agent; surface-modifying agent (comprising tensio-active agent); suspension agent or stablizer include, but is not limited to Magnesium Stearate; stearic acid; Sodium Lauryl Sulphate BP/USP; talcum powder; carbohydrate; lactose; dextrin; starch; gelatin; Mierocrystalline cellulose; methylcellulose gum; Microcrystalline Cellulose; sodium carboxy methyl cellulose; carboxy methyl cellulose calcium; polyvinylpyrrolidine; alginic acid; Sudan Gum-arabic; xanthan gum; Trisodium Citrate; composition silicate; lime carbonate; glycine; sucrose; Sorbitol Powder; Lin Suanergai; calcium sulfate; lactose; kaolin; mannitol; sodium-chlor; low melt wax and ion exchange resin.Surface-modifying agent comprises nonionic and anionic surface properties-correcting agent.The representative example of surface-modifying agent includes, but is not limited to poloxamer (poloxamer) 188, benzalkonium chloride (benzalkonium chloride), calcium stearate, cetostearyl alcohol (cetostearyl alcohol), cetomacrogol (cetomacrogol) emulsifying wax, sorbitan ester (sorbitan ester), colloidal silica, phosphoric acid salt, sodium lauryl sulphate, neusilin (magnesium aluminum silicate) and trolamine.Oral composite herein can utilize standard delay or time-delay to discharge the absorption that composite changes compound.Formula of oral also can be formed by throwing and containing the water of suitable solubilizing agent or emulsifying agent or the compound disclosed herein in the fruit juice on demand.
Can use liquid carrier to prepare solution, suspension, emulsion, syrup, elixir and carry out the inhaling type transmission.Compound of the present invention can dissolve or be suspended in pharmaceutically acceptable liquid carrier (for example water, organic solvent or both mixtures) or the pharmaceutically acceptable oils or fat.Described liquid carrier can contain other suitable auxiliary pharmaceutical adjuvant, for example solubilizing agent, emulsifying agent, damping fluid, sanitas, sweeting agent, seasonings, suspension agent, thickening material, tinting material, viscosity modifier, stablizer and Osmolyte regulator.The example that is used for the liquid carrier of oral and the outer dispensing of intestines includes, but is not limited to water and (especially contains additive as described herein, derivatived cellulose for example, sodium carboxy methyl cellulose solution for example), alcohols (comprises monohydroxy-alcohol and polyvalent alcohol, glycols for example) and its derivative and oils (for example, fractionated coconut oil and peanut oil).For the outer dispensing of intestines, supporting agent can be oily ester, for example ethyl oleate and isopropyl myristate.The sterile liquid supporting agent is the sterile liquid form composition that is used for for the outer dispensing of intestines.The liquid carrier that is used for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agent.
The liquid medical composition that is sterile solution or form of suspension can be used by for example intramuscular, intraperitoneal or subcutaneous injection.Sterile solution also can through intravenously throw with.The composition that is used for oral administration medicine supplying can be the liquid or solid form.
Medical composition preferably is unit dosage, for example tablet, capsule, powder, solution, suspension, emulsion, particle or suppository form.Under described form, medical composition can be further divided into the unitary dose that contains an amount of compound.Described unit dosage can be packaging compositions, for example packs powder, bottle, ampoule, pre-filled syringe or contains the anther sac of liquid.Perhaps, unit dosage can be capsule or tablet itself, and perhaps it can be any described composition that is packaged form of proper number.The compound that described unit dosage can contain the 1mg/kg that has an appointment is to the compound of about 500mg/kg, and can single dose or two or more dosage to.Described dosage can anyly be applicable to compound be directed to mode in recipient's blood flow throw with, that described mode comprises is oral, by implant, intestines (comprising intravenously, intraperitoneal and subcutaneous injection), per rectum, transvaginal and transdermal outward.
When for treatment or suppress the specified disease patient's condition or illness when offeing medicine, should be appreciated that the severity of visual used specific compound, dispensing pattern and the symptom for the treatment of of effective dose, and with treat the relevant multiple physical factors of individuality and change.In therapeutic is used, can provide the compound of the present invention of the amount of the symptom that is enough to cure or improve described disease and its complication to the patient who suffers from disease to small part.Desiring to be used for the treatment of the dosage of particular individual must determine by the doctor in charge is subjective usually.Related variable comprises very pathology and its patient's condition and patient's build, age and reaction type.
In some cases, be under the situation of target organs for example at lung, for example may need to use (but being not limited to) with inferior device directly compound is thrown with patient's tracheae in: metered-dose inhaler, breathe and handle sucker (breath-operatedinhaler), multidose dry powder inhaler, pump, squeeze-activated atomisation divider (squeeze-actuated nebulizedspray dispenser), aerosol dispenser and aerosol spraying gun.For by inhalation dosing in the nose or in the segmental bronchus, compound of the present invention can be deployed into liquid composition, solids composition or aerosol composition.Liquid composition can comprise (illustrating) one or more the dissolving, be partly dissolved or be suspended in one or more pharmaceutically acceptable solvents compound of the present invention and can by for example pump or squeeze-activated atomisation divider throw with.Described solvent can be for example to wait and oozes physiological saline or bacteriostatic water.Solids composition can be (illustrating) and comprises one or more compounds of the present invention and lactose or can be the powder formulation that uses the mixture of other inert powder of being accepted in the segmental bronchus, and can by for example aerosol dispenser or destruction or pierce through the capsule that encases described solids composition and transmit solids composition for the device that sucks throw with.Aerosol composition can comprise (illustrating) one or more compounds of the present invention, propelling agent, tensio-active agent and cosolvent, and can by for example measuring apparatus throw with.Described propelling agent can be acceptable other propelling agent on cfc (CFC), hydrofluoroalkane (HFA) or the physiology.
But compound intestines as herein described are outer or through intraperitoneal throw with.The solution of these compounds or its pharmaceutically acceptable salt, hydrate or ester or suspension can be with suitably preparing with tensio-active agent (for example hydroxyl-propyl cellulose) blended water.The oil solution preparation of the also available glycerine of dispersion liquid, liquid macrogol and its mixture.Under common storage and working conditions, these preparations contain the sanitas that is useful on the inhibition microorganism growth usually.
The medical form that is suitable for injecting can comprise aseptic aqueous solution or aqueous liquid dispersion and be used for preparing the sterilized powder of sterile injectable solution or dispersion liquid temporarily.In certain embodiments, described form can be aseptic and its viscosity makes it flow through syringe.Described form preferably make and holding conditions under stablize and can be protected and avoid the contamination of microorganism (for example bacterium and fungi).Supporting agent can be and contains for example solvent or the dispersion medium of water, ethanol, polyvalent alcohol (for example, glycerine, propylene glycol and liquid macrogol), its suitable mixture and vegetables oil.
But compound transdermal as herein described throw with, the inwall top layer (comprising epithelium and mucosal tissue) of promptly passing body surface and body passageway throw with.Described dispensing can use the compound of the present invention (comprising its pharmaceutically acceptable salt, hydrate or ester) in lotion, emulsifiable paste, foam, paster, suspension, solution and the suppository (rectum and vagina are used) to carry out.Transmit the local composite of compound of the present invention applicable to topical treatment of inflammation, psoriasis and sacroiliitis by epidermis.
Transdermal dispensing can contain compound (compound for example disclosed herein) and can be inertia, can be for skin nontoxic and can allow to transmit described compound and finish with the percutaneous plaster that absorbs the supporting agent in the blood flow by the skin general for described compound by use.Described supporting agent can adopt various ways, for example emulsifiable paste and ointment, paste, gel and blocking device.Emulsifiable paste and ointment can be oil-in-water or water-in-oil-type viscous liquid or semi-solid emulsion.Comprise the paste that is scattered in the oil that contains compound or the absorbent powder in the hydrophilic petroleum also can be suitable.Various blocking devices can be used for compound is discharged in the blood flow, for example cover to contain compound and to have or do not have preserving capsule or containing the semi-permeable membranes of the matrix of compound of supporting agent.Other blocking device is known in the literature.
Compound as herein described can conventional suppository the form per rectum or transvaginal throw with.The suppository composite can be by the conventional matter preparation that comprises theobroma oil (adding or do not add the wax that is used to change the suppository fusing point) and glycerine.Also can use water soluble suppository bases, for example various molecular weight polyethylene glycol.
Lipid composite or Nano capsule can be used for compound of the present invention in vitro or is in vivo introduced in the host cell.Lipid composite and Nano capsule can prepare by known method in the affiliated field.
For increasing the validity of compound of the present invention, may need compound and effectively other medicament combination of therapeutic goal disease.For instance, can with other active compound (that is, other activeconstituents or medicament) of effective therapeutic goal disease with compound of the present invention throw with.Described other medicament can with compound disclosed herein simultaneously or different time throw with.
Compound of the present invention is applicable to the pathology symptom or the illness of treatment, inhibition or prevention Mammals (for example human).Therefore, the invention provides treatment or suppress the pathology symptom or the method for illness, it is by providing compound of the present invention (or its pharmaceutically acceptable salt, hydrate or ester) or comprising one or more compounds of the present invention and the medical composition of pharmaceutically acceptable supporting agent carries out to Mammals.Compound of the present invention can throw separately with or throw with other treatment active compound or the therapy combination that is used for the treatment of or suppresses pathology symptom or illness and.As used herein, " treatment effectively " is meant the material or the amount that cause required biological activity or effect.As used herein, " treatment " be meant partially or completely and alleviate, suppress and/or improve symptom.
The present invention further comprise use compound disclosed herein and its pharmaceutically acceptable salt, hydrate and ester as the active treatment material with treatment, suppress or prevent mammiferous pathology symptom or illness.In certain embodiments, described pathology symptom or illness can be relevant with adhesion in the cell of selecting plain mediation.Therefore, the present invention further provides the method for using compounds for treating as herein described or preventing these pathology symptom and illness.
In certain embodiments, the invention provides adherent method in the cell that suppresses the plain mediation of the interior selection of mammalian body, it comprises compound of the present invention or its pharmaceutically acceptable salt, hydrate or ester to described Mammals throwing and significant quantity.In certain embodiments, the invention provides the interior adherent method of cell of the selection element mediation that suppresses relevant with disease, illness, symptom or improper process in the mammalian body, it comprises to described Mammals throws and the compound disclosed herein for the treatment of significant quantity.
In certain embodiments, described disease, illness, symptom or improper process can be infection, transfer, improper immunologic process, improper thrombosis process or have the disease or the symptom (for example, cardiovascular disorder, diabetes or rheumatoid arthritis) of inflammatory component.In certain embodiments, described disease, illness, symptom or improper process can be atherosclerosiss, the atherosclerosis thrombosis, restenosis, myocardial infarction, ischemia-reperfusion, Raynaud's syndrome, the inflammatory enteropathy, osteoarthritis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD), pulmonary emphysema, the lung inflammation, delayed hypersensitivity, idiopathic pulmonary fibrosis, cystic fibrosis, thermal damage, apoplexy, experimental allergic encephalomyelitis, wound Secondary cases multiple organ injury syndromes, neutrophilia tetter (Si Weiteshi disease), glomerulonephritis, ulcerative colitis, Crohn disease, necrotizing enterocolitis, the toxicity of cytokine induction, gingivitis, periodontitis, hemolytic uremic syndrome, psoriasis, systemic lupus erythematosus, the autoimmunity thyroiditis, multiple sclerosis, rheumatoid arthritis, the Ge Leifushi disease, the immune-mediated side effect of the treatment relevant with hemodialysis or leukopheresis, the granulocyte infusion syndromes of being correlated with, venous thrombosis, syndromes behind the thrombosis, unstable angina, transient ischemic attack, periphery vascular disease (for example peripheral arterial disease), the transfer relevant with cancer, sickle cell's syndromes (including, but is not limited to sicklemia), organ rejection response (graft versus host) or congestive heart failure.
In certain embodiments, disease, illness, symptom or improper process can be the improper course of infection by bacterium, virus or parasite mediation, for example relevant syndromes of gingivitis, periodontitis, hemolytic uremic syndrome or granulocyte infusion.
In certain embodiments, disease, illness, symptom or improper process can be the transfer relevant with cancer.In other embodiments, disease, illness, symptom or improper process can be disease or the illness relevant with improper immunologic process, for example the immune-mediated side effect of the treatment that psoriasis, systemic lupus erythematosus, autoimmunity thyroiditis, multiple sclerosis, rheumatoid arthritis, Ge Leifushi are sick and relevant with hemodialysis or leukopheresis.In certain embodiments, disease, illness, symptom or improper process can be and the relevant symptom of improper thrombosis process, for example syndromes, venous thromboembolism or congestive heart failure behind venous thrombosis, unstable angina, transient ischemic attack, peripheral vascular disease, the thrombosis.
In certain embodiments, the invention provides improve transplant organ (for example, the method for the improper immunologic process of renal transplantation thing, it comprises to described organ throws and compound of the present invention or its pharmaceutically acceptable salt, hydrate or ester.In certain embodiments, the invention provides the method for the treatment of or improving the symptom of sickle cell's syndromes (for example sicklemia), it comprises to the patient that needs are arranged throws and compound of the present invention.In certain embodiments, described method can comprise to be differentiated the mankind, Mammals or animal with the biomarker that relates to adherent disease in the cell of selecting plain mediation or illness and throws compound as herein described with the treatment significant quantity to the described mankind, Mammals or animal.In certain embodiments, described biomarker can be one or more in solubility palatelet-selectin, CD40, CD 40 parts, MAC-1, TGF β, ICAM, VCAM, IL-1, IL-6, IL-8, eotaxin (Eotaxin), RANTES, MCP-1, PIGF, CRP, SAA and the thrombocyte monocyte aggregate.
Compound of the present invention can by utilizing known standard synthetic method of those skilled in the art and program, be prepared by compound known in commercially available initial substance, the document or the easy intermediate for preparing according to the program of being summarized in the following flow process.Be used for that organic molecule preparation and functional group transform and the standard synthetic method of manipulation and program can be easily obtain from the related science document or from the standard textbook in affiliated field.Should be appreciated that,, unless otherwise prescribed, otherwise also can use other processing condition though provide typical case or preferred processing condition (that is, the mol ratio of temperature of reaction, time, reactant, solvent, pressure etc.).Optimum reaction condition can change with employed specific reactants or solvent, but described condition can be determined by the those skilled in the art by the optimization routine program.The technician in organic synthesis field will recognize, for the purpose of the formation of optimizing compound as herein described, can change the character and the order of the synthesis step that is presented.
Process as herein described can be monitored according to known any appropriate method in the affiliated field.For instance, can be (for example, by nuclear magnetic resonance spectrometry for example 1H or 13C), infrared spectroscopy, spectrophotometry are (for example, the UV-visible light), spectrography such as mass spectroscopy, or monitor product by for example high pressure lipuid chromatography (HPLC) (HPLC), vapor-phase chromatography (GC), gel permeation chromatography (GPC) or tlc (TLC) isochrome spectrometry and form.
The preparation of compound may relate to the protection of number of chemical group and go protection.To protection and de-protected needs with can easily determine by the those skilled in the art to the selection of due care base.The chemical property of protecting group can for example see Green people such as (Greene), the protecting group in the organic synthesis (Protective Groups in Organic Synthesis), the 2nd edition ((the Wiley ﹠amp of Willie father and son press; Sons), 1991) in, the whole disclosure of described document is incorporated herein by reference for all purposes.
Reaction as herein described or process can be carried out in suitable solvent, and described solvent can be easily selected by the technician in organic synthesis field.Suitable solvent usually in fact under the temperature of reacting (that is, can in the freezing temp of the solvent temperature in the scope of the boiling temperature of solvent) with reactant, intermediate and/or product reaction.Set reaction can be carried out in a kind of solvent or in the mixture of more than one solvents.Decide on specific reactions steps, can select to be suitable for the solvent of specific reactions steps.
Compound of the present invention generally can synthesize according to flow process 1-6.
Flow process 1
Figure G2008800104747D00281
Shown in above flow process 1, compound of the present invention can be by making the indoline-2 that randomly is substituted in the presence of alkali such as for example NaOH, and the 3-diketone reacts with acetate 2-oxo-propyl ester that randomly is substituted or correspondent alcohol and prepares, wherein n, R 3, R 3', R 4, R 5, R 6, R 7And R 8As defined herein.
Flow process 2
Figure G2008800104747D00282
Shown in above flow process 2, the indoline that is substituted-2, the 3-diketone can be by the aniline preparation that suitably is substituted, wherein R 3And R 3' as defined herein.
Flow process 3
Figure G2008800104747D00291
Perhaps, shown in above flow process 3, the indoline that is substituted-2, the 3-diketone can be by the aniline preparation that suitably is substituted, wherein R 3And R 3' as defined herein.
Flow process 4
Figure G2008800104747D00292
Shown in above flow process 4, the acetate 2-oxo-propyl ester that is substituted can be by the carboxylic acid preparation that suitably is substituted, wherein n, R 4, R 5, R 6, R 7And R 8As defined herein.
Flow process 5
Figure G2008800104747D00293
Perhaps, shown in above flow process 5, the acetate 2-oxo-propyl ester that is substituted can be by the halogenide preparation that suitably is substituted, wherein n, R 4, R 5, R 6, R 7And R 8As defined herein.
Flow process 6
Figure G2008800104747D00301
Perhaps, shown in above flow process 6, the correspondent alcohol of the acetate 2-oxo-propyl ester that is substituted can be by the carboxylic acid preparation that suitably is substituted, wherein n, R 4, R 5, R 6, R 7And R 8As defined herein.
Example
Only present following limiting examples the present invention is described.It will be understood by one of ordinary skill in the art that the equivalent and the variation that there are many not demonstrations but still form a part of the present invention.
The preparation intermediate
Preparation intermediate 1:1-chloro-3-methyl-3-phenyl fourth-2-ketone
Under nitrogen atmosphere, in the 250mL round-bottomed flask, add 2-methyl-2-phenylpropionic acid (5.0g, 30.9mmol, 1.0 equivalents) and 100mL methylene dichloride.In the gained stirred solution, add oxalyl chloride (3.2mL, 37.04mmol, 1.2 equivalents) and 3 dimethyl formamides (DMF).At room temperature stir the mixture and all stop to separate out up to all gas.Remove all volatile matter in a vacuum to produce oily solid.Under 0 ℃, make this material be dissolved in the 50mL anhydrous tetrahydro furan (THF) again and dropwise add in the ethereal solution of 100mL diazomethane.Make gained solution slowly be warmed up to room temperature and restir 12 hours.Make solution be cooled to 0 ℃ and make hydrogenchloride (HCl) gas bubbling in solution reach 5 minutes.Trash ice added in the mixture and continue stirred 15 minutes.Separate each layer and with two parts of 50mL extracted with diethyl ether water layers.The organic layer that merges with three parts of 100mL saturated sodium bicarbonate solutions, three parts of 100mL water and the washing of 100mL saturated nacl aqueous solution.Via dried over mgso solution, filter and remove in a vacuum solvent is colorless oil with generation intermediate 1 (5.73g, 94% productive rate). 1H?NMR(400MHz，CDCl 3)δ1.55(s，6H)，4.03(s，2H)，6.57-7.64(m，5H)。
Preparation intermediate 2: acetate 3-methyl-2-oxo-3-butyloxy phenyl
In 20mL microwave reaction bottle, add intermediate 1 (1-chloro-3-methyl-3-phenyl fourth-2-ketone, 5.73g, 29.16mmol, 1.0 equivalents) and 15mL acetone.In gained solution, add acetate (2.2mL, 37.9mmol, 1.3 equivalents) and triethylamine (5.3mL, 37.9mmol, 1.3 equivalents).Seal described bottle and in microwave reactor, be heated to 150 ℃ and continue 30 minutes.Gained suspension poured in the 200mL water and with three parts of 100mL ethyl acetate extractions.Organic layer with three parts of 250mL water and 250mL saturated nacl aqueous solution washing merging.Via the dried over mgso organic layer, filter and remove solvent to produce brown oil.Come this oily matter of purifying with the generation solid intermediate 2 (4.75g, 74% productive rate) that is white in color by silica gel chromatography (Biotage Flash 40,0-10% ethyl acetate/hexane). 1H?NMR(400MHz，CDCl 3)δ1.55(s，6H)，2.10(s，3H)，4.56(s，2H)，6.58-7.98(m，5H)。
Preparation intermediate 3:6,7,8,9-tetrahydrochysene-1H-benzo [g] indoles-2,3-diketone
Use by poplar people such as (Yang) ( Referring toJACS (J.Am.Chem.Soc), 1996,118:9557) described isatin is synthetic.With Chloral Hydrate (3.28g, 19.8mmol), oxammonium hydrochloride (4.13g, 59.4mmol) and sodium sulfate (23g 165mmol) puts into the 500mL round-bottomed flask, and adds 120mL water.At N 2Under the balloon suspension is heated to 55 ℃ and all dissolves, and add 5,6,7,8-tetrahydrochysene-naphthalene-1-base amine (Aldrich company (Aldrich), 2.43g, 16.5mmol) emulsion in the 2M aqueous hydrochloric acid up to all solids.Continue heating whole night.After 18 hours, make the reaction mixture cool to room temperature.Collect brown block throw out by filtering, wash with water, and drying is whole night to generate isonitrosoacetanilide (3.4g).Under 65 ℃, under agitation, isonitrosoacetanilide (3.4g) is divided into aliquot adds in the 12.4mL vitriol oil in the round-bottomed flask.After adding all isonitrosoacetanilides, under 85 ℃,, and pour on the trash ice in the beaker atropurpureus solution stirring 10 minutes.Add ice again, can feel cold up to touching the beaker outside.By filtering orange-brown throw out of collection and drying, carry out purifying by extraction whole night to generate isatin 3.Extract intermediates 3 (5.7g) and abandon insoluble solid with three parts of 400mL hot ethyl acetates.The evaporation of acetic acid ethyl ester produces the 3.83g pure substance. 1H NMR (400MHz, methyl-sulphoxide-d 6(" DMSO-d 6")) δ 1.74 (m, 4H), 2.50 (m, 2H), 2.74 (t, J=5.81Hz, 2H), 6.79 (d, J=7.83Hz, 1H), 7.23 (d, J=7.83Hz, 1H), 10.95 (s, 1H).
Preparation intermediate 4:6,7-dimethyl-1H-indoles-2,3-diketone
Use by thunder Karst people such as (Rewcastle) ( Referring toMedical chemistry magazine (J.Med.Chem.), 1991,34:217) described isatin is synthetic.With Chloral Hydrate (45g, 0.27mol), oxammonium hydrochloride (205g, 1.25mol) and sodium sulfate (226.5g 1.6mol) puts into the 2L round-bottomed flask, and adds 750mL water.In this suspension, add 250mL contain concentrated hydrochloric acid (HCl, the 23 dimethyl aniline in water 25mL) (29.05g, 0.24mol).At N 2Down, under 45 ℃, added hot suspension 90 minutes, with after be heated to 52 ℃ in 45 minutes, and 75 ℃ of heating 60 minutes down.Make the reaction mixture cool to room temperature.By filtering the collecting precipitation thing, water and petroleum ether, and in vacuum drier drying whole night to generate thick N-(2,3-dimethyl-phenyl)-2-oxyimino-ethanamide (40.1g, 87%).
Under 70 ℃-80 ℃, in 1 hour, under agitation (20g 0.1mol) is divided into aliquot and adds 80mL CH to N-(2,3-dimethyl-phenyl)-2-oxyimino-ethanamide 3SO 3Among the H.After finishing interpolation, it was kept 15 minutes under uniform temp and pour on the trash ice in the beaker.Adding ice again can feel cold up to touching the beaker outside.Collecting precipitation thing and being dissolved in the 1N NaOH aqueous solution.With precipitated impurities and acidifying (HCl) filtrate that the acetate neutralization removes by filtration, generation is solid intermediate 4 (12.8g, 70% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ2.09(s，3H)，2.27(s，3H)，6.89(d，J＝7.58Hz，1H)，7.25(d，J＝7.58Hz，1H)，11.02(s，1H)。
Preparation intermediate 5:7-isopropyl indole quinoline-2, the 3-diketone
Prepare the intermediate 5 (46% productive rate) that is brown ceramic powder according to the program that is used for intermediate 3. 1H NMR (400MHz, DMSO-d 6) δ 1.18 (d, J=6.8Hz, 6H), 3.04 (septet, 1H), 7.06 (t, J=7.7Hz, 1H), 7.35 (d, J=7.3Hz, 1H), 7.54 (d, J=7.3Hz, 1H), 11.09 (s, 1H).MS (electron spray(ES)) 188 (M-H) -
Preparation intermediate 7:2-chloro-1-(1-phenycyclopropyl) ethyl ketone
Under nitrogen atmosphere, in the 250mL round-bottomed flask, add 1-phenyl cyclopropane-carboxylic acid (5.0g, 30.9mmol, 1.0 equivalents) and 100mL methylene dichloride.In the gained stirred solution, add oxalyl chloride (3.2mL, 37.04mmol, 1.2 equivalents) and 3 DMF.At room temperature stir the mixture and all stop to separate out up to all gas.Remove all volatile matter in a vacuum to generate oily solid.Make this material be dissolved among the anhydrous THF of 50mL again and dropwise add in the ethereal solution of the 100mL diazomethane that is cooled to 0 ℃.Make gained solution slowly be warmed up to room temperature and stirred 12 hours.Make solution be cooled to 0 ℃ and make HCl gas bubbling in solution reach 5 minutes once more.Trash ice added in the mixture and continue stirred 15 minutes.Separate each layer and with two parts of 50mL extracted with diethyl ether water layers.The organic layer that merges with three parts of 100mL saturated sodium bicarbonate solutions, three parts of 100mL water and the washing of 100mL saturated nacl aqueous solution.Via dried over mgso solution, filter and remove in a vacuum solvent is colorless oil with generation intermediate 7 (3.71g, 61% productive rate). 1H?NMR(400MHz，CDCl 3)δ1.28(q，J＝3.79Hz，2H)，1.73(q，J＝3.37Hz，2H)，4.11(s，2H)，6.58-7.80(m，5H)。
Preparation intermediate 8: acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester
In 20mL microwave reaction bottle, add intermediate 7 (2-chloro-1-(1-phenycyclopropyl) ethyl ketone, 3.71g, 19.07mmol, 1.0 equivalents) and 15mL acetone.In gained solution, add acetate (1.41mL, 24.8mmol, 1.3 equivalents) and triethylamine (3.5mL, 24.8mmol, 1.3 equivalents).Seal described bottle and in microwave reactor, be heated to 150 ℃ and continue 30 minutes.Gained suspension poured in the 200mL water and with three parts of 100mL ethyl acetate extractions.Organic layer with three parts of 250mL water and 250mL saturated nacl aqueous solution washing merging.Via the dried over mgso organic layer, filter and remove solvent generating brown oil, come the described oily matter of purifying with the generation required product of the solid (intermediate 8 that is white in color by silica gel chromatography (Biotage Flash 40,0-10% ethyl acetate/hexane), 1.51g, 36% productive rate). 1H?NMR(400MHz，CDCl 3)δ1.24(q，J＝3.54Hz，2H)，1.69(q，J＝3.54Hz，2H)，2.11(s，3H)，4.57(s，2H)，6.35-8.47(m，5H)。
Preparation intermediate 9:2-(oxyimino)-N-(2-iodophenyl) ethanamide
According to above for intermediate 3 described programs, make 2-Iodoaniline (10g, 46mmol) with Chloral Hydrate (9.1g, 55mmol), oxammonium hydrochloride (11.4g, 0.165mol) and sodium sulfate (52g, 0.366mol) reaction is 2-(oxyimino)-N-(2-iodophenyl) ethanamide (11.0g, 83% productive rate) of beige solid with generation. 1H?NMR(400MHz，DMSO-d 6)δ6.99(t，J＝7.7Hz，1H)，7.41(t，1H)，7.63(s，1H)，7.76(dd，J＝8.1，1.3Hz，1H)，7.90(dd，J＝7.8，1.3Hz，1H)，9.38(s，1H)，12.42(s，1H)。
Preparation intermediate 10:7-iodine indoline-2, the 3-diketone
For intermediate 3 described programs, (11.0g is 38.0mmol) to generate garnet powder (intermediate 10,8.30g, 80% productive rate) for 2-(oxyimino)-N-(2-iodophenyl) ethanamide in the heating 30mL vitriol oil according to above. 1H?NMR(400MHz，DMSO-d 6)δ6.89(t，J＝7.7Hz，1H)，7.50(d，J＝7.3Hz，1H)，7.95(d，J＝6.8Hz，1H)，11.01(s，1H)。
Preparation intermediate 11:7-Phenylindole quinoline-2, the 3-diketone.
According to by agile this base people such as (Lisowski) ( Referring toOrganic chemistry magazine (J.Org.Chem.), 2000,65:4193) described program.Add 7-iodine indoline-2 in the 1L 3 neck round-bottomed flasks that are equipped with reflux exchanger, (7.33mmol) (0.424g 0.367mmol), adds 225mL 1, the 2-glycol dimethyl ether to the 3-diketone subsequently with four [triphenylphosphine] palladium for intermediate 10,2.0g.By with vacuum communicating, be communicated with positive pressure of nitrogen three times subsequently, make the atmosphere in the reaction vessel be inertia.Add phenyl-boron dihydroxide (Aldrich company (Aldrich), 0.983g, 8.06mmol) and sodium bicarbonate (1.23g, the 14.7mmol) solution in 225mL water, and repeat the evacuation/nitrogen purge program once more.The reacting by heating mixture shows 7-iodine indoline-2,3-diketone completely dissolve (1-2 hour) up to tlc (t.l.c) (10% ethyl acetate in the methylene dichloride) under reflux temperature.Behind the cool to room temperature, under reduced pressure remove 1, the 2-glycol dimethyl ether.With 1M aqueous hydrochloric acid dilution resistates and in ethyl acetate, extract.With salt water washing organic layer, via anhydrous magnesium sulfate drying and filtration.Under reduced pressure remove ethyl acetate to generate thick 7-Phenylindole quinoline-2,3-diketone.
Repeat this program 8 times again.Come crude product that purifying merges to be the pure 7-Phenylindole quinoline-2 of orange needle-like crystal, 3-diketone (by 18g 7-iodine indoline-2, the 3-diketone obtains for 10.94g, 74% productive rate) by flash chromatography on silica gel method (dichloromethane solution of 1% ethyl acetate) with generation. 1H?NMR(400MHz，DMSO-d 6)δ7.18(t，J＝7.6Hz，1H)，7.48(m，6H)，7.59(d，J＝8.8Hz，1H)，10.91(s，1H)。
Preparation intermediate 12:2-(oxyimino)-N-(2-(trifluoromethoxy) phenyl) ethanamide.
Prepare intermediate 12 (85% productive rate) according to the program that is used for intermediate 3. 1H?NMR(400MHz，DMSO-d 6)δ7.31(m，1H)，7.42(m，2H)，7.75(s，1H)，7.97(dd，J＝7.8，1.3Hz，1H)，9.71(s，1H)，12.39(s，1H)。
Preparation intermediate 13:7-(trifluoromethoxy) indoline-2, the 3-diketone.
According to by Ma Weier people such as (Marvel) ( Referring toOrganic synthesis accumulation volume (Org.Synth.Coll.) volume I, 327) described program.Under 55 ℃, (11.9g 48.5mmol) is divided into aliquot and adds in the 35mL vitriol oil in the 250mL erlenmeyer flask (Erlenmeyer flask) with intermediate 12.Solution temperature is remained on below 70 ℃ up to adding all ethanamides, and make it be elevated to 80 ℃ to continue 10 minutes.Make the dark solution cool to room temperature and pour on the 175mL trash ice.After leaving standstill 30 minutes,, wash with water three times, and drying has the indoline-2 that is enough to be used in the purity in the next step with generation, 3-diketone (intermediate 13,8.32g, 70% productive rate) under vacuum by filtering the collecting precipitation thing. 1H?NMR(400MHz，DMSO-d 6)δ7.15(t，J＝7.8Hz，1H)，7.56(d，J＝7.3Hz，1H)，7.64(d，J＝8.3Hz，1H)，11.71(s，1H)。
Preparation intermediate 14:N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl) phenyl)-2-(oxyimino) ethanamide
In the 250mL round-bottomed flask, add 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoro propan-2-ol (2.0g, 7.72mmol, 1.0 equivalent), Chloral Hydrate (1.53g, 9.27mmol, 1.2 equivalents), oxammonium hydrochloride (1.9g, 27.02mmol, 3.5 equivalent), sodium sulfate (10.97g, 77.22mmol, 10.0 equivalents), 50mL water and 12mL 1.2N HCl.With gained mixture heating up to 55 ℃ and stirred 15 hours.Make gained suspension cool to room temperature and obtain sedimentary oxime intermediate 14 by filtering.
Preparation intermediate 15:5-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl) indoline-2, the 3-diketone
Add to thick intermediate 14 in the 20mL vitriol oil and be heated to 80 ℃ and continue 10 minutes.The 200mL trash ice is added in this redness/brown mixture and stir gained suspension 30 minutes.Be the required product (intermediate 15,1.25g, 52% productive rate) of yellow solid with generation by solid collected by filtration and by silica gel chromatography (Biotage Flash 40,25% ethyl acetate/hexane) purifying. 1H?NMR(400MHz，DMSO-d 6)δ7.08(d，J＝8.59Hz，1H)，7.52-7.70(m，2H)，7.77-7.93(m，1H)，8.93(s，1H)。
Preparation intermediate 16:7-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl) indoline-2, the 3-diketone
In the 500mL round-bottomed flask, add 2-(2-aminophenyl)-1,1,1,3,3,3-hexafluoro propan-2-ol (9.0g, 34.75mmol, 1.0 equivalent), Chloral Hydrate (6.9g, 41.69mmol, 1.2 equivalents), oxammonium hydrochloride (8.45g, 122.0mmol, 3.5 equivalent), sodium sulfate (49.34g, 347.0mmol, 10.0 equivalents), 225mL water and 55mL 1.2NHCl.With gained mixture heating up to 55 ℃ and stirred 15 hours.Make gained suspension cool to room temperature and obtain sedimentary oxime intermediate by filtering.Add to this white solid in the 20mL vitriol oil and be heated to 80 ℃ and continue 10 minutes.Trash ice (200mL) is added in this redness/brown mixture and stir gained suspension 30 minutes.Be the required product (intermediate 16,5.64g, 52% productive rate) of yellow solid with generation by solid collected by filtration and by silica gel chromatography (Biotage Flash 40,25% ethyl acetate/hexane) purifying. 1H?NMR(400MHz，CDCl 3)δ7.22(dd，J＝8.34，7.33Hz，1H)，7.69(d，J＝9.35Hz，1H)，7.75(dd，J＝7.33，1.26Hz，1H)。
Preparation intermediate 17:2-chloro-1-(1-(4-p-methoxy-phenyl) cyclopropyl) ethyl ketone
Under nitrogen atmosphere, in the 25mL round-bottomed flask, add 1-(4-p-methoxy-phenyl) cyclopropane-carboxylic acid (0.96g, 5.0mmol, 1.0 equivalents) and 5mL methylene dichloride.Add oxalyl chloride (0.6mL, 6.5mmol, 1.3 equivalents) and 1 DMF, and stir the mixture and all stop to separate out up to all gas.Remove all volatile matters in a vacuum and the gained resistates is dissolved among the 5mL THF again.This solution is dropwise added in the ethereal solution of the 20mL diazomethane that is cooled to 0 ℃.Make gained solution slowly be warmed up to room temperature and stirred 12 hours.Make solution be cooled to 0 ℃ and make HCl gas therein bubbling reach 3 minutes.Trash ice added in the mixture and continue stirred 15 minutes.Separate each layer and with two parts of 50mL extracted with diethyl ether water layers.The organic layer that merges with three parts of 100mL saturated sodium bicarbonate solutions, three parts of 100mL water and the washing of 100mL saturated nacl aqueous solution.Via dried over mgso solution, filter and remove in a vacuum solvent is colorless oil with generation intermediate 17 (0.327g, 30% productive rate). 1H?NMR(400MHz，CDCl 3)δ1.20(q，J＝3.54Hz，2H)，1.66(q，J＝3.37Hz，2H)，3.82(s，3H)，4.32(s，2H)，6.89(d，J＝8.84Hz，2H)，7.34(d，J＝8.84Hz，2H)。
Preparation intermediate 18: acetate 2-(1-(4-p-methoxy-phenyl) cyclopropyl)-2-oxo ethyl ester
In 20mL microwave reaction bottle, add intermediate 17 (2-chloro-1-(1-(4-p-methoxy-phenyl) cyclopropyl) ethyl ketone, 0.327g, 1.48mmol, 1.0 equivalents) and 5mL acetone.In gained solution, add acetate (0.11mL, 1.92mmol, 1.3 equivalents) and triethylamine (0.27mL, 1.92mmol, 1.3 equivalents).Seal described bottle and in microwave reactor, descend heating 30 minutes at 150 ℃.Gained suspension poured in the 50mL water and with three parts of 25mL ethyl acetate extractions.Organic layer with three parts of 75mL water and 75mL saturated nacl aqueous solution washing merging.Via the dried over mgso organic layer, filter and remove solvent to generate brown oil.Come this oily matter of purifying with the generation required product of solid (intermediate 18,0.144g, 40% productive rate) that is white in color by silica gel chromatography (Biotage Flash 40,0-10% ethyl acetate/hexane). 1H?NMR(400MHz，CDCl 3)δ1.20(q，J＝3.54Hz，2H)，1.66(q，J＝3.37Hz，2H)，2.11(s，3H)，3.82(s，3H)，4.58(s，2H)，6.89(d，J＝8.84Hz，2H)，7.34(d，J＝8.84Hz，2H)。
Preparation intermediate 19:1-(4-(trifluoromethyl) phenyl) cyclopropane formonitrile HCN
According to by Yue Enqike people such as (Jonczyk) ( Referring toInternational organic preparation procedure (Org.Prep.Proc.Int.), 1995,27 (3): 355-359) described program prepares this compound.In the 25mL round-bottomed flask that is equipped with condenser, add 2-(4-(trifluoromethyl) phenyl) acetonitrile (0.75g, 4.05mmol, 1.0 equivalents), 1-bromo-2-monochloroethane (0.50mL, 6.08mmol, 1.5 equivalent) and chlorination triethylbenzene ammonium methyl (0.018g, 0.08mmol, 0.02 equivalent).With gained mixture heating up to 50 ℃ and dropwise add sodium hydroxide (6.0 equivalents are dissolved in the 1.0mL water for 0.97g, 24.0mmol).Mixture was stirred 16 hours down at 50 ℃.Make its cool to room temperature and pour in the 50mL water.With three parts of these suspension of 25mL dichloromethane extraction and the organic layer that merges with three parts of 50mL 1.2N HCl aqueous solution, three parts of 50mL water and the washing of 50ml saturated nacl aqueous solution.Via the dried over mgso organic layer, filter and remove in a vacuum solvent.Come the thick material of purifying to be the required product (intermediate 19,0.74g, 86% productive rate) of faint yellow oily thing with generation by silica gel chromatography (Biotage Flash 40,10% ethyl acetate/hexane). 1H?NMR(400MHz，CDCl 3)δ1.41-1.53(m，2H)，1.78-1.87(m，2H)，7.40(d，J＝8.34Hz，2H)，7.62(d，J＝8.34Hz，2H)。
Preparation intermediate 20:1-(4-(trifluoromethyl) phenyl) cyclopropane-carboxylic acid
In the 50mL round-bottomed flask that is equipped with condenser, add the intermediate 19 (1-(4-(trifluoromethyl) phenyl) cyclopropane formonitrile HCN, 0.55g, 2.5mmol, 1.0 equivalents) and the 20mL4.0N LiOH aqueous solution.Heating this suspension and stirring 15 hours under reflux temperature.Make gained mixture cool to room temperature and pour in the 250mL 1.2N HCl solution.Wash the organic layer that merges with three parts of these suspension of 75mL ethyl acetate extraction and with three parts of 200mL water and 200mL saturated nacl aqueous solution.Via the dried over mgso organic layer, filter and remove in a vacuum solvent.The acquisition required product of solid (intermediate 20,0.564g, 95% productive rate) that is white in color. 1H?NMR(400MHz，CDCl 3)δ1.29(q，J＝3.87Hz，2H)，1.72(q，J＝3.87Hz，2H)，7.46(d，J＝8.08Hz，2H)，7.57(d，J＝8.08Hz，2H)。
Preparation intermediate 21:2-hydroxyl-1-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone
In the 50mL round-bottomed flask that is equipped with condenser, add intermediate 20 (1-(4-(trifluoromethyl) phenyl) cyclopropane-carboxylic acid, 0.270g, 1.18mmol, 1.0 equivalents) and 25mL thionyl chloride.Heating this mixture and stirring 4 hours under reflux temperature.Make its cool to room temperature and remove all volatile matters in a vacuum.In the gained yellow oil, add three (trimethylsiloxy group) ethene (0.757g, 2.59mmol, 2.2 equivalents) and with mixture heating up to 80 ℃, and stirred 12 hours.In this mixture, add the solution of 15mL 1.2N HCl solution, 10mL water and 35mL diox.Heating this mixture and stirring 1 hour under reflux temperature.After cooling, immediately with three parts of 50mL ethyl acetate extraction mixtures and the organic layer that merges with three parts of 100mL saturated sodium bicarbonate solutions, three parts of 100mL water and the washing of 100mL saturated nacl aqueous solution.Via the dried over mgso organic layer, filter and remove in a vacuum solvent.Come the thick oily matter of purifying to be the required product (intermediate 21,0.149g, 52% productive rate) of colorless oil with generation by silica gel chromatography (Biotage Flash 40,10-25% ethyl acetate/hexane). 1H?NMR(400MHz，CDCl 3)δ1.32(q，J＝3.96Hz，2H)，1.79(q，J＝3.79Hz，2H)，4.05(s，2H)，7.51(d，J＝7.83Hz，2H)，7.64(d，J＝8.08Hz，2H)。
Preparation intermediate 22:1-(4-bromophenyl) cyclopropane formonitrile HCN
By being used for the method for intermediate 19, use 2-(4-bromophenyl) acetonitrile (0.79g, 4.05mmol, 1.0 equivalents), 1-bromo-2-monochloroethane (0.50mL, 6.08mmol, 1.5 the ammonium methyl of chlorination triethylbenzene equivalent), (0.018g, 0.08mmol, 0.02 equivalent) and sodium hydroxide (0.97g, 24.0mmol, 6.0 equivalent is dissolved in the 1.0mL water) come synthetic mesophase thing 22 as initial substance.The acquisition required product of solid (intermediate 22,0.55g, 61% productive rate) that is white in color. 1HNMR(400MHz，CDCl 3)δ1.33-1.44(m，2H)，1.68-1.79(m，2H)，7.16(d，J＝8.59Hz，2H)，7.48(d，J＝8.84Hz，2H)。
Preparation intermediate 23:1-(4-bromophenyl) cyclopropane-carboxylic acid
By being used for the method for intermediate 20, use 1-(4-bromophenyl) cyclopropane formonitrile HCN (0.548g, 2.5mmol, 1.0 equivalents) to come synthetic mesophase thing 23 as initial substance.The acquisition required product of solid (intermediate 23,0.56g, 95% productive rate) that is white in color. 1H?NMR(400MHz，CDCl 3)δ1.23(q，J＝3.96Hz，2H)，1.58-1.71(m，2H)，7.21(d，J＝8.34Hz，2H)，7.43(d，J＝8.34Hz，2H)。
Preparation intermediate 24:1-(1-(4-bromophenyl) cyclopropyl)-2-chloroethene ketone
In the 50mL round-bottomed flask that is equipped with condenser, add intermediate 23 (1-(4-bromophenyl) cyclopropane-carboxylic acid, 0.255g, 1.06mmol, 1.0 equivalents) and 25mL thionyl chloride.Heating gained solution and stirring 4 hours under reflux temperature.Behind cool to room temperature, remove all volatile matters immediately in a vacuum.Make the gained brown oil be dissolved among the 10mL THF again and dropwise add in the ethereal solution of the 100mL diazomethane that is cooled to 0 ℃.Make this mixture slowly be warmed up to room temperature and stirred 12 hours.Make solution be cooled to 0 ℃ and make HCl gas therein bubbling reach 3 minutes.Trash ice added in the mixture and continue stirred 15 minutes.Separate each layer and with two parts of 50mL extracted with diethyl ether water layers.The organic layer that merges with three parts of 100mL saturated sodium bicarbonate solutions, three parts of 100mL water and the washing of 100mL saturated nacl aqueous solution.Via dried over mgso solution, filter and remove in a vacuum solvent is colorless oil with generation intermediate 24 (0.287g, 100% productive rate). 1H?NMR(400MHz，CDCl 3)δ1.25(q，J＝3.96Hz，2H)，1.74(q，J＝3.62Hz，2H)，4.08(s，2H)，7.28(d，J＝8.59Hz，2H)，7.52(d，J＝8.34Hz，2H)。
Preparation intermediate 25: acetate 2-(1-(4-bromophenyl) cyclopropyl)-2-oxo ethyl ester
By being used for the method for intermediate 18, use intermediate 24 (1-(1-(4-bromophenyl) cyclopropyl)-2-chloroethene ketone, 0.287g, 1.06mmol, 1.0 equivalent), acetate (0.08mL, 1.4mmol, 1.3 equivalents) and triethylamine (0.3mL, 1.3mmol, 1.3 equivalents) and come synthetic mesophase thing 25 as initial substance.The acquisition required product of solid (intermediate 25,0.091g, 30% productive rate) that is white in color. 1H?NMR(400MHz，CDCl 3)δ1.21(q，J＝3.87Hz，2H)，1.69(q，J＝3.79Hz，2H)，2.11(s，3H)，4.55(s，2H)，7.31(d，J＝8.59Hz，2H)，7.51(d，J＝8.59Hz，2H)。
Preparation intermediate 26:1-(3-chloro-phenyl-) cyclopropane formonitrile HCN
By being used for the method for intermediate 19, use 2-(3-chloro-phenyl-) acetonitrile (1.0g, 6.6mmol, 1.0 1-bromo-2-monochloroethane (0.82mL equivalent),, 9.9mmol, 1.5 equivalent) and chlorination triethylbenzene ammonium methyl (0.030g, 0.13mmol, 0.02 equivalent) come synthetic mesophase thing 26 as initial substance.Acquisition is the required product (intermediate 26,1.2g, 100% productive rate) of yellow oil. 1H?NMR(400MHz，CDCl 3)δ1.36-1.45(m，2H)，1.69-1.81(m，2H)，6.38-7.94(m，5H)。
Preparation intermediate 27:1-(3-chloro-phenyl-) cyclopropane-carboxylic acid
By being used for the method for intermediate 20, using intermediate 26 (1-(3-chloro-phenyl-) cyclopropane formonitrile HCN, 1.2g, 6.6mmol, 1.0 equivalents) to come synthetic mesophase thing 27, and obtain to be white in color solid intermediate 27 (0.81g, 62% productive rate) as initial substance.This material is converted into intermediate 28 and need not other analysis.
Preparation intermediate 28:1-(1-(3-chloro-phenyl-) cyclopropyl)-2-hydroxyl ethyl ketone
By being used for the method for intermediate 21, use intermediate 27 (1-(3-chloro-phenyl-) cyclopropane-carboxylic acid, 0.81g, 4.08mmol, 1.0 equivalents), thionyl chloride (20mL, excessive in a large number) and three (trimethylsiloxy group) ethene (2.64g, 9.0mmol, 2.2 equivalent) come synthetic mesophase thing 28, and obtain to be the intermediate 28 (0.396g, 46% productive rate) of colorless oil as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.30(q，J＝3.79Hz，2H)，1.74(q，J＝3.62Hz，2H)，3.16(t，J＝4.67Hz，1H)，4.08(d，J＝4.80Hz，2H)，5.97-8.14(m，4H)。
Preparation intermediate 29:1-(2-chloro-phenyl-) cyclopropane formonitrile HCN
By being used for the method for intermediate 19, use 2-(2-chloro-phenyl-) acetonitrile (1.0g, 6.6mmol, 1.0 equivalent), 1-bromo-2-monochloroethane (0.82mL, 9.9mmol, 1.5 equivalents) and chlorination triethylbenzene ammonium methyl (0.030g, 0.13mmol, 0.02 equivalent) come synthetic mesophase thing 29, and obtain to be the intermediate 29 (1.2g, 100% productive rate) of yellow oil as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.31-1.38(m，2H)，1.71-1.79(m，2H)，6.55-7.78(m，4H)。
Preparation intermediate 30:1-(2-chloro-phenyl-) cyclopropane-carboxylic acid
By being used for the method for intermediate 20, using intermediate 26 (1-(3-chloro-phenyl-) cyclopropane formonitrile HCN, 1.2g, 6.6mmol, 1.0 equivalents) to come synthetic mesophase thing 30, and obtain to be white in color solid intermediate 30 (1.045g, 90% productive rate) as initial substance.This material is converted into intermediate 31 and need not other analysis.
Preparation intermediate 31:2-chloro-1-(1-(2-chloro-phenyl-) cyclopropyl) ethyl ketone
By being used for the method for intermediate 24, use intermediate 30 (1-(2-chloro-phenyl-) cyclopropane-carboxylic acid, 1.05g, 6.6mmol, 1.0 equivalent), thionyl chloride (20mL, excessive) and diazomethane (100mL ethereal solution, excessive) come synthetic mesophase thing 31 as initial substance, and obtain to be the intermediate 31 (1.03g, 68% productive rate) of yellow oil. 1H?NMR(400MHz，CDCl 3)δ1.30(d，J＝3.79Hz，2H)，1.86(d，J＝3.79Hz，2H)，4.11(s，2H)，6.78-7.81(m，4H)。
Preparation intermediate 32: acetate 2-(1-(2-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester
By being used for the method for intermediate 25, use intermediate 31 (2-chloro-1-(1-(2-chloro-phenyl-) cyclopropyl) ethyl ketone, 1.03g, 4.5mmol, 1.0 equivalents), acetate (0.34mL, 5.85mmol, 1.3 equivalent) and triethylamine (0.81mL, 5.85mmol, 1.3 equivalents) come synthetic mesophase thing 32 as initial substance, and obtain to be brown solid intermediate 32 (0.36g, 32% productive rate). 1H?NMR(400MHz，CDCl 3)δ1.26(d，J＝3.79Hz，2H)，1.82(d，J＝3.79Hz，2H)，2.11(s，3H)，4.59(s，2H)，7.28-7.35(m，2H)，7.39-7.53(m，2H)。
Preparation intermediate 33:1-(4-(trifluoromethoxy) phenyl) cyclopropane formonitrile HCN
By being used for the method for intermediate 19, use 2-(4-(trifluoromethoxy) phenyl) acetonitrile (1.0g, 4.97mmol, 1.0 1-bromo-2-monochloroethane (0.62mL equivalent),, 7.5mmol, 1.5 equivalents) and chlorination triethylbenzene ammonium methyl (0.023g, 0.10mmol, 0.02 equivalent) come synthetic mesophase thing 33, and obtain to be the intermediate 33 of yellow oil as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.22-1.49(m，2H)，1.66-1.85(m，2H)，7.20(d，J＝7.83Hz，2H)，7.33(d，J＝8.84Hz，2H)。
Preparation intermediate 34:1-(4-(trifluoromethoxy) phenyl) cyclopropane-carboxylic acid
By being used for the method for intermediate 20, use intermediate 26 (1-(3-chloro-phenyl-) cyclopropane formonitrile HCN, 1.14g, 4.97mmol, 1.0 equivalents) and come synthetic mesophase thing 34 as initial substance, and obtain to be white in color solid intermediate 34 (0.895g, 73% productive rate is through 2 steps). 1H?NMR(400MHz，CDCl 3)δ1.20-1.30(m，2H)，1.55-1.77(m，2H)，7.14(d，J＝8.08Hz，2H)，7.36(d，J＝8.59Hz，2H)。
Preparation intermediate 35:2-hydroxyl-1-(1-(4-(trifluoromethoxy) phenyl) cyclopropyl) ethyl ketone
By being used for the method for intermediate 21, use intermediate 34 (1-(4-(trifluoromethoxy) phenyl) cyclopropane-carboxylic acid, 0.895g, 3.64mmol, 1.0 equivalents), thionyl chloride (20mL, excessive in a large number) and three (trimethylsiloxy group) ethene (2.34g, 8.0mmol, 2.2 equivalent) come synthetic mesophase thing 35, and obtain to be the intermediate 35 (0.527g, 56% productive rate) of colorless oil as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.30(q，J＝3.71Hz，2H)，1.76(q，J＝3.62Hz，2H)，3.16(t，J＝4.29Hz，1H)，4.05(d，J＝4.29Hz，2H)，7.22(d，J＝7.83Hz，2H)，7.41(d，J＝8.84Hz，2H)。
Preparation intermediate 36:1-(3-(trifluoromethyl) phenyl) cyclopropane formonitrile HCN
By being used for the method for intermediate 19, use 2-(3-(trifluoromethyl) phenyl) acetonitrile (1.0g, 5.4mmol, 1.0 1-bromo-2-monochloroethane (0.67mL equivalent),, 8.1mmol, 1.5 equivalents) and chlorination triethylbenzene ammonium methyl (0.024g, 0.11mmol, 0.02 equivalent) come synthetic mesophase thing 36, and obtain to be the intermediate 36 of yellow oil as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.43-1.49(m，2H)，1.77-1.86(m，2H)，7.40-7.62(m，4H)。
Preparation intermediate 37:1-(3-(trifluoromethyl) phenyl) cyclopropane-carboxylic acid
By being used for the method for intermediate 20, use intermediate 36 (1-(3-(trifluoromethyl) phenyl) cyclopropane formonitrile HCN, 1.15g, 5.4mmol, 1.0 equivalents) and come synthetic mesophase thing 37 as initial substance, and obtain to be white in color solid intermediate 37 (1.03g, 82% productive rate is through 2 steps). 1H?NMR(400MHz，CDCl 3)δ1.26-1.32(m，2H)，1.64-1.77(m，2H)，7.42(t，J＝7.71Hz，1H)，7.49-7.57(m，2H)，7.59(s，1H)。
Preparation intermediate 38:2-hydroxyl-1-(1-(3-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone
By being used for the method for intermediate 21, use intermediate 37 (1-(3-(trifluoromethyl) phenyl) cyclopropane-carboxylic acid, 1.03g, 4.5mmol, 1.0 equivalents), thionyl chloride (20mL, excessive in a large number) and three (trimethylsiloxy group) ethene (2.88g, 9.85mmol, 2.2 equivalent) come synthetic mesophase thing 38, and obtain to be the intermediate 38 (0.687g, 62% productive rate) of colorless oil as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.34(q，J＝3.87Hz，2H)，1.80(q，J＝3.62Hz，2H)，3.17(t，J＝4.80Hz，1H)，4.04(d，J＝4.80Hz，2H)，7.40-7.70(m，4H)。
Preparation intermediate 39:1-chloro-3-phenyl fourth-2-ketone
By being used for the method for intermediate 1, use 2-phenylpropionic acid (3.29g, 21.91mmol, 1.0 equivalent) and oxalyl chloride (2.3mL, 26.3mmol, 1.2 equivalents) come synthetic mesophase thing 39 as initial substance, and obtain to be the intermediate 39 (3.80g, 95% productive rate) of colorless oil.This material is converted into intermediate 40 and need not other analysis.
Preparation intermediate 40: acetate 2-oxo-3-butyloxy phenyl
By being used for the method for intermediate 2, use intermediate 39 (1-chloro-3-phenyl fourth-2-ketone, 3.80g, 20.8mmol, 1.0 equivalents), acetate (1.6mL, 27.0mmol, 1.3 equivalent) and triethylamine (3.8mL, 27.0mmol, 1.3 equivalents) come synthetic mesophase thing 40 as initial substance, and obtain to be wax shape brown solid intermediate 40 (3.4g, 79% productive rate). 1H?NMR(400MHz，CDCl 3)δ1.44(d，J＝7.07Hz，3H)，2.12(s，3H)，3.81(q，J＝7.07Hz，1H)，4.52(d，J＝16.67Hz，1H)，4.69(d，J＝16.67Hz，1H)，7.17-7.41(m，5H)。
Perhaps, can be by following program synthetic mesophase thing 40.Under inert atmosphere, (25mL 12.5mmol) puts into flame-dried 100mL 2 neck round-bottomed flasks with the THF solution of 0.5M bromination (1-phenylethyl) zinc (II).Make reaction mixture be cooled to 0 ℃, and add Pd (PPh 3) 4(0.288g, 0.25mmol), subsequently via syringe dropwise add chloroacetyl chloride among the 6mL THF (1.5mL, 18.8mmol).At room temperature with the brown suspension stirred overnight.For reacting, add 12mL 1M hydrochloric acid and with four parts of 12mL ethyl acetate extraction mixtures.With the organic layer of salt water washing merging, via anhydrous MgSO 4Drying is filtered and is concentrated.According to the program that is used for intermediate 21 this thick material is converted into intermediate 40.
Preparation intermediate 41:2-chloro-1-(1-(4-chloro-phenyl-) cyclobutyl) ethyl ketone
By being used for the method for intermediate 1, use 1-(4-chloro-phenyl-) cyclobutane formate (2.0g, 9.50mmol, 1.0 equivalent) and oxalyl chloride (1.0mL, 11.40mmol, 1.2 equivalent) come synthetic mesophase thing 41, and obtain to be the intermediate 41 (2.30g, 100% productive rate) of colorless oil as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.70-2.09(m，2H)，2.34-2.51(m，2H)，2.66-3.00(m，2H)，4.00(s，2H)，7.18(d，J＝8.84Hz，2H)，7.36(d，J＝8.84Hz，2H)。
Preparation intermediate 42: acetate 2-(1-(4-chloro-phenyl-) cyclobutyl)-2-oxo ethyl ester
By being used for the method for intermediate 2, use intermediate 41 (2-chloro-1-(1-(4-chloro-phenyl-) cyclobutyl) ethyl ketone, 2.3g, 9.5mmol, 1.0 equivalents), acetate (0.71mL, 12.35mmol, 1.3 equivalent) and triethylamine (1.72mL, 12.35mmol, 1.3 equivalents) come synthetic mesophase thing 42 as initial substance, and obtain to be wax shape brown solid intermediate 42 (1.69g, 67% productive rate). 1H?NMR(400MHz，CDCl 3)δ1.74-2.04(m，2H)，2.12(s，3H)，2.33-2.49(m，2H)，2.68-2.97(m，2H)，4.47(s，2H)，7.18(d，J＝8.34Hz，2H)，7.35(d，J＝8.34Hz，2H)。
Preparation intermediate 43:1-(thiene-3-yl-) cyclopropane formonitrile HCN
By being used for the method for intermediate 19, use 2-(thiene-3-yl-) acetonitrile (1.0g, 8.12mmol, 1.0 equivalent), 1-bromo-2-monochloroethane (1.0mL, 12.18mmol, 1.5 equivalents) and chlorination triethylbenzene ammonium methyl (0.037g, 0.16mmol, 0.02 equivalent) come synthetic mesophase thing 43, and obtain to be the intermediate 43 (0.34g, 28% productive rate) of colorless oil as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.27-1.41(m，2H)，1.62-1.74(m，2H)，6.91(dd，J＝5.05，1.26Hz，1H)，7.18(dd，J＝3.03，1.52Hz，1H)，7.31(dd，J＝5.05，3.03Hz，1H)。
Preparation intermediate 44:1-(thiene-3-yl-) cyclopropane-carboxylic acid
By being used for the method for intermediate 20, using intermediate 43 (1-(thiene-3-yl-) cyclopropane formonitrile HCN, 0.34g, 2.27mmol, 1.0 equivalents) to come synthetic mesophase thing 44, and obtain to be white in color solid intermediate 44 (0.356g, 93% productive rate) as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.17-1.31(m，2H)，1.62-1.70(m，2H)，7.09(dd，J＝5.05，1.01Hz，1H)，7.16(dd，J＝3.03，1.26Hz，1H)，7.21-7.29(m，1H)。
Preparation intermediate 45:2-hydroxyl-1-(1-(thiene-3-yl-) cyclopropyl) ethyl ketone
By being used for the method for intermediate 21, use intermediate 44 (1-(thiene-3-yl-) cyclopropane-carboxylic acid, 0.356g, 2.12mmol, 1.0 equivalent) and three (trimethylsiloxy group) ethene (1.54mL, 4.66mmol, 2.2 equivalents) come synthetic mesophase thing 45 as initial substance, and obtain to be the intermediate 45 (0.062g, 16% productive rate) of colorless oil. 1HNMR(400MHz，CDCl 3)δ1.29(q，J＝3.54Hz，2H)，1.69(q，J＝3.54Hz，2H)，3.15(t，J＝4.80Hz，1H)，4.15(d，J＝4.80Hz，2H)，7.05(dd，J＝5.05，1.26Hz，1H)，7.23(dd，J＝3.03，1.52Hz，1H)，7.34(dd，J＝4.93，2.91Hz，1H)。
Preparation intermediate 46:1-(thiophene-2-yl) cyclopropane formonitrile HCN
By being used for the method for intermediate 19, use 2-(thiophene-2-yl) acetonitrile (1.0g, 8.12mmol, 1.0 1-bromo-2-monochloroethane (1.0mL equivalent),, 12.18mmol, 1.5 equivalent) and chlorination triethylbenzene ammonium methyl (0.037g, 0.16mmol, 0.02 equivalent) come synthetic mesophase thing 46 as initial substance.Acquisition is the required product (intermediate 46,1.20g, 100% productive rate) of colorless oil. 1H?NMR(400MHz，CDCl 3)δ1.37-1.49(m，2H)，1.67-1.82(m，2H)，6.94(dd，J＝5.18，3.66Hz，1H)，7.06(dd，J＝3.54，1.26Hz，1H)，7.19(dd，J＝5.05，1.26Hz，1H)。
Preparation intermediate 47:1-(thiophene-2-yl) cyclopropane-carboxylic acid
By being used for the method for intermediate 20, use intermediate 46 (1-(thiophene-2-yl) cyclopropane formonitrile HCN, 1.20g, 8.12mmol, 1.0 equivalents) to come synthetic mesophase thing 47 as initial substance.The acquisition required product of solid (intermediate 47,1.16g, 85% productive rate) that is white in color. 1H?NMR(400MHz，CDCl 3)δ1.40(q，J＝3.96Hz，2H)，1.77(q，J＝3.87Hz，2H)，6.90-6.93(m，1H)，6.96(dd，J＝3.54，1.26Hz，1H)，7.20(dd，J＝5.05，1.26Hz，1H)。
Preparation intermediate 48:2-hydroxyl-1-(1-(thiophene-2-yl) cyclopropyl) ethyl ketone
By being used for the method for intermediate 21, use intermediate 47 (1-(thiophene-2-yl) cyclopropane-carboxylic acid, 1.16g, 6.9mmol, 1.0 equivalent) and three (trimethylsiloxy group) ethene (5.0mL, 15.2mmol, 2.2 equivalents) come synthetic mesophase thing 48 as initial substance.Acquisition is the required product (intermediate 48,0.387g, 31% productive rate) of colorless oil. 1H?NMR(400MHz，CDCl 3)δ1.43(q，J＝3.79Hz，2H)，1.80(q，J＝3.54Hz，2H)，3.12(t，J＝4.80Hz，1H)，4.28(d，J＝4.80Hz，2H)，6.99(dd，J＝5.31，3.54Hz，1H)，7.04(dd，J＝3.54，1.26Hz，1H)，7.28(dd，J＝5.31，1.26Hz，1H)。
Preparation intermediate 49:1-(4-fluorophenyl) cyclopropane formonitrile HCN
(wherein make an amendment slightly by the method that is used for intermediate 19, promptly 50 ℃ of following stirred reaction mixtures 5 days), use 2-(4-fluorophenyl) acetonitrile (2.0g, 14.8mmol, 1.0 equivalent), 1-bromo-2-monochloroethane (2.45mL, 29.6mmol, 2.0 equivalents) and chlorination triethylbenzene ammonium methyl (0.067g, 0.3mmol, 0.02 equivalent) and come synthetic mesophase thing 49 as initial substance.Acquisition is the required product (intermediate 49,1.52g, 63% productive rate) of colorless oil. 1H?NMR(400MHz，CDCl 3)δ1.27-1.42(m，2H)，1.56-1.80(m，2H)，6.94-7.10(m，2H)，7.19-7.40(m，2H)。
Preparation intermediate 50:1-(4-fluorophenyl) cyclopropane-carboxylic acid
By being used for the method for intermediate 20, using intermediate 49 (1-(4-fluorophenyl) cyclopropane formonitrile HCN, 1.52g, 9.32mmol, 1.0 equivalents) to come synthetic mesophase thing 50, and obtain to be white in color solid intermediate 50 (1.64g, 98% productive rate) as initial substance. 1H?NMR(400MHz，CDCl 3)δ1.23(q，J＝4.04Hz，2H)，1.66(q，J＝4.04Hz，2H)，6.91-7.04(m，2H)7.21-7.38(m，2H)。
Preparation intermediate 51:1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone
By being used for the method for intermediate 21, use intermediate 50 (1-(4-fluorophenyl) cyclopropane-carboxylic acid, 1.64g, 9.11mmol, 1.0 equivalent) and three (trimethylsiloxy group) ethene (6.6mL, 20.0mmol, 2.2 equivalents) come synthetic mesophase thing 51 as initial substance, and obtain to be the intermediate 51 (0.824g, 47% productive rate) of colorless oil. 1H?NMR(400MHz，CDCl 3)δ1.28(q，J＝3.79Hz，2H)，1.74(q，J＝3.71Hz，2H)，3.18(t，J＝4.67Hz，1H)，4.04(d，J＝4.55Hz，2H)，6.93-7.17(m，2H)，7.27-7.46(m，2H)。
Preparation intermediate 52:1-chloro-3-(4-chloro-phenyl-) fourth-2-ketone
Under 25 ℃, (2.4g, 13.0mmol) (1.23mL is 14.3mmol) with 2 DMF for middle interpolation oxalyl chloride for the 2-in 50mL THF (4-chloro-phenyl-) propionic acid.Stir the gained mixture 1.5 hours and concentrated the chloride of acid that is faint yellow oily thing with generation.The diethyl ether solution that is dissolved in described faint yellow oily thing among the 20mLTHF and dropwise adds the 40mL diazomethane in the 250mL erlenmeyer flask under 0 ℃ is (according to organic synthesis accumulation volume (Org.Syn.Coll.), 1943, the method preparation described in the 2:165) in.Cover described flask with a slice aluminium foil pine loose ground.Under 25 ℃, gently stir the mixture whole night.Under 0 ℃, make HCl gas bubbling in reaction mixture reach 5 minutes.Stirring gained solution 1 hour and concentrated to generate the oiliness resistates is transferred to described resistates the mixture elution of also using 150mL ethyl acetate/hexane (1: 4) in the filter funnel that silica gel is housed under 0 ℃.Concentrated filtrate is 1-chloro-3-(4-chloro-phenyl-) fourth-2-ketone of faint yellow oily thing, intermediate 52 with generation. 1H?NMR(400MHz，CDCl 3)δ1.44(d，J＝7.1Hz，3H)，3.67(s，2H)，4.04(q，J＝7.1Hz，1H)，7.10-7.52(m，4H)。
Preparation intermediate 53: acetate 3-(4-chloro-phenyl-)-2-oxo butyl ester
Make above-mentioned oily matter be dissolved in the 50mL acetone and be cooled to 0 ℃.Add acetate (0.89mL, 15.6mmol) and triethylamine (2.17mL, 15.6mmol).Make the gained mixture be warmed up to 25 ℃ and stirred 2 days.Remove white depositions via filtration.Concentrated filtrate is to generate the oiliness resistates, by column chromatography (silica gel, ethyl acetate: hexane=1: 5) come the described resistates of purifying, obtain being the required product (intermediate 53,1.7g, 54% productive rate) of faint yellow oily thing. 1H?NMR(400MHz，CDCl 3)δ1.42(d，J＝7.3Hz，3H)，2.12(s，3H)，3.81(q，J＝7.3Hz，1H)，4.53(d，J＝17.1Hz，1H)，4.68(d，J＝17.1Hz，1H)，7.16(d，J＝8.0Hz，2H)，7.32(d，J＝8.0Hz，2H)。
Preparation intermediate 54:7-(thiene-3-yl-) indoline-2, the 3-diketone
According to synthetic described program, make 7-iodine indoline-2,3-diketone (10 for intermediate 11,2.0g, 7.33mmol) with four [triphenylphosphine] palladium (0.424g, 0.367mmol), subsequently with 3 thienylboronic acid (Aldrich company (Aldrich), 1.03g, 8.06mmol) reaction.Come the thick material 54 of purifying to generate bright red crystalline material (54% productive rate) by flash chromatography on silica gel method (3% ethyl acetate in the methylene dichloride). 1H?NMR(400MHz，DMSO-d 6)δ7.15(t，1H)，7.36(dd，J＝4.9，1.4Hz，1H)，7.50(dt，J＝7.3，1.0Hz，1H)，7.68(d，J＝1.5Hz，1H)，7.71(m，2H)，7.75(dd，J＝2.9，1.4Hz，1H)，10.86(s，1H)。
Preparation intermediate 55: acetate 2-(1-(4-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester
Come synthetic mesophase thing 55 according to the program that is used for intermediate 40, wherein make 1-(4-chloro-phenyl-) cyclopropane-carboxylic acid (2.4g, 12.2mmol) and oxalyl chloride (1.15mL, 13.4mmol) react to generate 2-chloro-1-(1-(4-chloro-phenyl-) cyclopropyl) ethyl ketone, make and generate material and acetate (1.78mL, 31.2mmol) and triethylamine (4.34mL, 31.2mmol) reaction is the required product (1.4g, 46% productive rate) of faint yellow oily thing with generation.
2-chloro-1-(1-(4-chloro-phenyl-) cyclopropyl) ethyl ketone. 1H?NMR(400MHz，CDCl 3)δ1.26(dd，J＝7.1，3.4Hz，2H)，1.74(dd，J＝7.1，3.4Hz，2H)，4.08(s，2H)，7.34-7.36(m，4H)。
Acetate 2-(1-(4-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester (intermediate 55). 1H?NMR(400MHz，CDCl 3)δ1.21(dd，J＝6.6，3.4Hz，2H)，1.70(dd，J＝6.6，3.4Hz，2H)，2.11(s，3H)，4.54(s，2H)，7.33-7.40(m，4H)。
Preparation intermediate 56: acetate 3-(4-chloro-phenyl-)-3-methyl-2-oxo butyl ester
Come synthetic mesophase thing 56 according to the program that is used for intermediate 40, wherein make 2-(4-chloro-phenyl-)-2 Methylpropionic acid (5.9g, 29.8mmol) and oxalyl chloride (2.6mL, 32.8mmol) react to generate 1-chloro-3-(4-chloro-phenyl-)-3-methyl fourth-2-ketone, make and generate material and acetate (2.67mL, 46.8mmol) and triethylamine (6.51mL, 46.8mmol) reaction is the required product (0.7g, 9.2% productive rate) of colorless oil with generation.
1-chloro-3-(4-chloro-phenyl-)-3-methyl fourth-2-ketone. 1H?NMR(400MHz，CDCl 3)δ1.54(s，6H)，4.02(s，2H)，7.27(d，J＝8.9Hz，2H)，7.37(d，J＝8.9Hz，2H)。
Acetate 3-(4-chloro-phenyl-)-3-methyl-2-oxo butyl ester (intermediate 56). 1H?NMR(400MHz，CDCl 3)δ1.53(s，6H)，2.11(s，3H)，4.56(s，2H)，7.20-7.37(m，4H)。
Preparation intermediate 57:1-hydroxyl-3-phenyl penta-2-ketone
Under 115 ℃, (2.0g is 12.2mmol) with the mixture heating up of 7mL thionyl chloride in 15mL toluene 16 hours with the 2-phenylbutyric acid.Concentrated reaction mixture produces the oiliness resistates.In this resistates, add 10mL toluene and concentrated gained mixture to generate yellow oil.With 1,1, (8.0mL 24.4mmol) adds in the described yellow oil 2-three (trimethylsiloxy group) ethane.Under nitrogen atmosphere, in 100 ℃ of following reacting by heating mixtures 16 hours.Under 50 ℃, add 10mL diox and 2mL 1N HCl.Stirred the gained mixture 2 hours down at 80 ℃.Enriched mixture produces yellow oiliness resistates.Add 10mL water and 15mL ether.With saturated sodium bicarbonate solution and the salt water washing organic layer of each 5mL, and via dried over mgso.Remove solid via filtration.Concentrated filtrate obtains being the required product (intermediate 57,1.74g, 80% productive rate) of yellow oil, and described product need not to be further purified promptly and can be used in the next step. 1H?NMR(400MHz，CDCl 3)δ0.85(t，J＝7.2Hz，3H)，1.77-1.88(m，1H)，2.09-2.17(m，1H)，3.52(t，J＝7.2Hz，1H)，4.21(d，J＝4.9Hz，2H)，7.18-7.37(m，5H)。
Preparation intermediate 58:1-(1,2-dihydro cyclobutene acene time first-1-yl)-2-hydroxyl ethyl ketone
Come synthetic mesophase thing 58 according to the program that is used for intermediate 57, wherein make 1-benzocyclobutane zinecarboxylic acid (1.0g, 6.76mmol) and 3.5mL thionyl chloride and 1,1,2-three (trimethylsiloxy group) ethane (4.4mL, 13.34mmol) reaction is the required product (0.55g, 65% productive rate) of colorless oil with generation. 1H?NMR(400MHz，CDCl 3)δ2.82-2.98(m，1H)，3.05-3.20(m，1H)，3.46-3.51(m，1H)，4.44-4.47(m，2H)，7.05-7.81(m，4H)。
Preparation intermediate 59:1-hydroxy-4-methyl-3-phenyl penta-2-ketone
Come synthetic mesophase thing 59 according to the program that is used for intermediate 57, wherein make 3-methyl-2-phenylbutyric acid (1.0g, 5.60mmol) and 3.5mL thionyl chloride and 1,1,2-three (trimethylsiloxy group) ethane (3.7mL, 11.2mmol) reaction is the required product (0.65g, 60% productive rate) of colorless oil with generation. 1H?NMR(400MHz，CDCl 3)δ0.71(d，J＝6.8Hz，3H)，0.98(d，J＝6.8Hz，3H)，2.43-2.55(m，1H)，3.26(d，J＝10.7Hz，1H)，4.18(d，J＝19.2Hz，1H)，4.27(d，J＝19.2Hz，1H)，7.21-7.34(m，5H)。
Preparation intermediate 60:1-hydroxy-3-methyl-4-phenyl fourth-2-ketone
Come synthetic mesophase thing 60 according to the program that is used for intermediate 57, wherein make 2-methyl-3-phenylpropionic acid (1.0g, 6.1mmol) and 3.5mL thionyl chloride and 1,1,2-three (trimethylsiloxy group) ethane (4.0mL, 12.2mmol) reaction is the required product (0.70g, 64% productive rate) of colorless oil with generation. 1H?NMR(400MHz，CDCl 3)δ1.16(d，J＝7.0Hz，3H)，2.68(dd，J＝13.3，7.0Hz，1H)，2.76-2.89(m，1H)，2.99(dd，J＝13.3，7.6Hz，1H)，3.94(dd，J＝19.3，4.2Hz，1H)，4.24(dd，J＝19.3，4.2Hz，1H)，7.18-7.32(m，5H)。
Preparation intermediate 61: hydroxy-4-phenyl penta-2-ketone
Come synthetic mesophase thing 61 according to the program that is used for intermediate 44, wherein make 3-phenylbutyric acid (1.0g, 6.1mmol) and 3.5mL thionyl chloride and 1,1,2-three (trimethylsiloxy group) ethane (4.0mL, 12.2mmol) reaction is the required product (0.80g, 74% productive rate) of colorless oil with generation. 1H?NMR(400MHz，CDCl 3)δ1.30(d，J＝7.0Hz，3H)，2.64(dd，J＝15.7，7.1Hz，1H)，2.73(dd，J＝15.7，7.1Hz，1H)，3.01(t，J＝4.4Hz，1H)，3.30-3.42(m，1H)，4.01(dd，J＝19.2，4.4Hz，1H)，4.14(dd，J＝19.2，4.4Hz，1H)，7.17-7.34(m，5H)。
Preparation intermediate 62:N-(2-ethylphenyl)-2-(oxyimino) ethanamide
According to the described program of above first step, make 2-ethylaniline (2.0mL, 2.0g for intermediate 3,16.5mmol) and Chloral Hydrate (3.28g, 19.8mmol), oxammonium hydrochloride (4.13g, 59.4mmol) and sodium sulfate (23g, 165mmol) reaction to generate block brown precipitate thing.
Preparation intermediate 63:7-ethylindole quinoline-2, the 3-diketone
According to by poplar people such as (Yang) ( Referring toJACS (J.Am.Chem.Soc), 1996,118:9557) described program.Intermediate 62 worn into powder and under agitation be divided into aliquot add in the 15mL vitriol oil that has been heated to 90 ℃ in the 50mL erlenmeyer flask.Slowly add ethanamide so that the temperature of reaction mixture remains on below 105 ℃.After finishing interpolation, under 90 ℃,, be cooled to 60 ℃, and pour on the 15g trash ice in the beaker atropurpureus solution stirring 15 minutes.Adding ice again can feel cold up to touching the beaker outside.By filter to collect orange-brown throw out and dryly under vacuum have the indoline-2 that is enough to be used in the purity in the next step with generation whole night, 3-diketone (intermediate 63,0.77g, 27% productive rate).Also can make intermediate 63 recrystallize in ethanol be the pure products of orange red spicule with generation. 1H?NMR(400MHz，DMSO-d 6)δ1.14(t，J＝7.5Hz，3H)，2.56(q，J＝7.6Hz，2H)，7.03(t，J＝7.5Hz，1H)，7.35(d，J＝7.3Hz，1H)，7.46(d，J＝7.6Hz，1H)，11.11(s，1H)。
Preparation intermediate 64:N-(2-secondary butyl phenenyl)-2-(oxyimino) ethanamide
According to the described program of above first step for intermediate 3, make 2-sec-butyl aniline (10.4mL, 10g, 67mmol) with Chloral Hydrate (13.3g, 80.4mmol), oxammonium hydrochloride (16.8g, 0.241mol) and sodium sulfate (76g 0.54mol) reacts.Product does not precipitate with solid form, therefore with three parts of ethyl acetate extraction refrigerative reaction mixtures, and with salt water washing ethyl acetate solution, via anhydrous magnesium sulfate drying, filter and under reduced pressure concentrate and have the intermediate 64 that is enough to be used in the purity in the cyclisation step and is viscosity dark-brown oily matter with generation. 1H?NMR(400MHz，DMSO-d 6)δ0.75(t，J＝7.3Hz，3H)，1.14(d，J＝6.8Hz，3H)，1.51(m，2H)，2.86(m，1H)，7.24(m，4H)，7.68(s，1H)，9.57(s，1H)，12.16(s，1H)。
Preparation intermediate 65:7-sec-butyl indoline-2, the 3-diketone
For carrying out cyclisation, the 50mL vitriol oil is added in the round-bottomed flask that contains intermediate 64, and under agitation with the situation of air communication under mixture heating up to 80 ℃ is continued 30 minutes.Make gained mixture cool to room temperature, pour on the 250mL trash ice, and it was left standstill 30 minutes.By filtering the collecting precipitation thing, wash with water three times, and drying has the indoline-2 that is enough to be used in the purity in the next step with generation, 3-diketone (52% productive rate is obtained by 2-sec-butyl aniline for intermediate 65,7.03g) under vacuum. 1H?NMR(400MHz，DMSO-d 6)δ0.81(t，J＝7.3Hz，3H)，1.17(d，J＝6.8Hz，3H)，1.55(m，2H)，2.83(m，1H)，7.06(t，J＝7.6Hz，1H)，7.36(d，J＝7.1Hz，1H)，7.51(d，J＝7.6Hz，1H)，11.09(s，1H)。
Preparation intermediate 66:N-(2-tert-butyl-phenyl)-2-(oxyimino) ethanamide
According to the described program of above first step, make 2-tertiary butyl aniline (10.4mL, 10.0g for intermediate 3,67.0mmol) and Chloral Hydrate (13.3g, 80.4mmol), oxammonium hydrochloride (16.8g, 0.241mol) and sodium sulfate (114g, 0.804mol) reaction.With ethyl acetate extraction refrigerative reaction mixture and evaporation, produce thick ethanamide (intermediate 66,13.6g, 92% productive rate) with the purity that is enough to be used in the next step.
Preparation intermediate 67:7-tertiary butyl indoline-2, the 3-diketone
, for intermediate 65 described programs intermediate 66 is heated with the 45mL vitriol oil according to above.Acquisition has the indoline-2 that is enough to be used in the purity in the next step, 3-diketone (intermediate 67,6.92g, 55% productive rate). 1HNMR(400MHz，DMSO-d 6)δ1.32(s，9H)，7.04(t，1H)，7.39(d，J＝7.3Hz，1H)，7.55(dd，J＝7.8，1.3Hz，1H)，10.76(s，1H)。
Preparation intermediate 68:N-(2-fluorophenyl)-2-(oxyimino) ethanamide.
According to the described program of above first step for intermediate 3, sodium sulfate (128g, 0.900mol) exist make down the 2-fluoroaniline (8.7mL, 10g, 90mmol) with Chloral Hydrate (17.9g, 0.108mol) and oxammonium hydrochloride (22.5g 0.324mol) reacts.Collect pure intermediate 68 and drying (11.7g, 71% productive rate) under vacuum by filtering. 1H?NMR(400MHz，DMSO-d 6)δ7.20(m，2H)，7.29(m，1H)，7.74(s，1H)，7.86(m，1H)，9.81(s，1H)，12.30(s，1H)。
Preparation intermediate 69:7-fluoro indole quinoline-2, the 3-diketone
For intermediate 63 described programs, heat the intermediate 68 (11.7g) in the 60mL vitriol oil according to above.The indoline-2 that obtains, the 3-diketone has the purity (intermediate 69,6.87g, 65% productive rate) that is enough to be directly used in the next step. 1H?NMR(400MHz，DMSO-d 6)δ7.08(ddd，1H)，7.38(dt，J＝7.5，0.8Hz，1H)，7.54(ddd，J＝10.4，8.3，1.0Hz，1H)，11.56(s，1H)。
Preparation intermediate 70:N-(2-bromophenyl)-2-(oxyimino) ethanamide.
According to the described program of above first step for intermediate 3, sodium sulfate (99g, 0.70mol) exist make down the 2-bromaniline (10g, 58mmol) with Chloral Hydrate (11.5g, 69.7mmol) and oxammonium hydrochloride (14.5g 0.209mol) reacts.Collect block brown precipitate thing by filtering, and under vacuum dry (intermediate 70,11.98g, 85% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ7.16(t，1H)，7.41(t，J＝7.7Hz，1H)，7.69(m，2H)，7.91(d，J＝8.1Hz，1H)，9.46(s，1H)，12.45(s，1H)。
Preparation intermediate 71:7-bromo indole quinoline-2, the 3-diketone
For intermediate 13 described programs, (3.11g is 12.8mmol) to generate sorrel powder (intermediate 71,2.22g, 77% productive rate) for the intermediate 70 in the heating 10mL vitriol oil according to above. 1H?NMR(400MHz，DMSO-d 6)δ7.02(t，J＝7.8Hz，1H)，7.52(d，J＝6.6Hz，1H)，7.79(d，J＝8.1Hz，1H)，11.32(s，1H)。
Preparation intermediate 72:2-(oxyimino)-N-(2-aminomethyl phenyl) ethanamide
According to the described program of above first step for intermediate 3, at sodium sulfate (133g, 0.933mol) make Ortho Toluidine (10mL under existing, 10g, 93mmol) with Chloral Hydrate (19g, 0.11mol) and oxammonium hydrochloride (23g, 0.34mol) reaction is the intermediate 72 (10.9g, 65% productive rate) of fine hair shape pale powder with generation.
Preparation intermediate 73:7-skatole quinoline-2, the 3-diketone
For intermediate 13 described programs, the intermediate 72 in the heating 45mL vitriol oil is to generate orange powder (intermediate 73,5.96g, 61% productive rate) according to above. 1H?NMR(400MHz，DMSO-d 6)δ2.19(s，3H)，6.99(t，J＝7.6Hz，1H)，7.34(d，J＝7.6Hz，1H)，7.43(d，J＝7.6Hz，1H)，11.09(s，1H)。
Preparation intermediate 74:2-(oxyimino)-N-(3-aminomethyl phenyl) ethanamide
According to the described program of above first step for intermediate 3, at sodium sulfate (133g, 0.933mol) make meta-aminotoluene (10mL under existing, 10g, 93mmol) with Chloral Hydrate (19g, 0.11mol) and oxammonium hydrochloride (23g, 0.34mol) reaction is to generate intermediate 74 (14.4g, 87% productive rate).
Preparation intermediate 75 and 76:6-skatole quinoline-2,3-diketone/4-skatole quinoline-2,3-diketone
For intermediate 13 described programs, the intermediate 74 in the heating 60mL vitriol oil is the 6-methyl isatin of orange powder and the inextricable mixture of 4-methyl isatin (intermediate 75 and 76,3.44g, 26% productive rate) with generation according to above. 1H?NMR(400MHz，DMSO-d 6)δ2.35(s，1.5H)，2.44(s，1.5H)，6.71(m，1H)，6.87(t，1H)，7.42(m，1H)，10.99(s，1H)。
Preparation intermediate 77:2-hydroxyl-1-(1-p-methylphenyl-cyclopropyl)-ethyl ketone
According to the program that is used for intermediate 51, use 1-p-methylphenyl-cyclopropane-carboxylic acid to prepare intermediate 77 as initial substance.Crude mixture is delivered to next step.
Preparation intermediate 78:1-(1-(4-chloro-phenyl-) cyclopropyl)-2-hydroxyl ethyl ketone
In the 1L round-bottomed flask, (20g 0.10mol) is dissolved in the 175mL toluene to make 1-(4-chloro-phenyl-) cyclopropane-carboxylic acid.(heated solution is whole night under reflux temperature 1.0mol) and under nitrogen for 75mL, 122g to add thionyl chloride.After the cooling, remove toluene and excessive thionyl chloride, and make itself and other three parts of 100mL methylbenzene azeotropics by evaporation.Under nitrogen, (67mL, 59g 0.20mol) heat whole night together with described chloride of acid and three (trimethylsiloxy group) ethene under 100 ℃.Make reaction mixture be cooled to 50 ℃ and with 100mL 1,4-diox and the dilution of 20mL 1M hydrochloric acid subsequently.Heated the gained mixture 2 hours down at 80 ℃.Under reduced pressure remove organic solvent and with 150mL water dilution remaining mixture, and with three parts of extracted with diethyl ether.Organic layer with two part of 5% sodium carbonate solution washing merges via anhydrous magnesium sulfate drying, filters and concentrates to generate yellow oil (intermediate 78,17.9g, 83% productive rate).Can further come this oily matter of purifying by flash chromatography on silica gel method (the 6-50% ethyl acetate in the hexane). 1H?NMR(400MHz，CDCl 3)δ1.28(q，J＝4.0Hz，2H)，1.74(q，J＝3.5Hz，2H)，3.16(t，J＝4.7Hz，1H)，4.05(d，J＝4.8Hz，2H)，7.29-7.32(m，2H)，7.33-7.37(m，2H)。
Preparation intermediate 79: iodo-7-(trifluoromethyl) indoline-2,3-diketone
According to draw by C. Maas (C.Lamas), J. Baruch pacify lattice people such as (J.Barluenga) ( Referring toOrganic chemistry magazine (J.Org.Chem.), 1996,61:5804) described iodate method.(8.79g 40.9mmol) is dissolved in the 105mL anhydrous methylene chloride in the 500mL round-bottomed flask to make intermediate 6.Add two (pyridine) iodine (I) tetrafluoride boron (23g, 61mmol), add subsequently trifluoromethayl sulfonic acid (10.8mL, 18.4g, 0.123mol).At room temperature stirred the mixture 40 minutes, and analyzed the completely dissolve of demonstration initial substance up to LC-MS.With the 105mL water treatment solution and with two parts of 45mL dichloromethane extractions.Organic layer with the washing of 5% sodium thiosulfate solution merges via anhydrous magnesium sulfate drying, filters and concentrates to generate pure products (intermediate 79,12.0g, 87% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ8.03(s，1H)，8.11(s，1H)，11.55(s，1H)。
Preparation intermediate 80:5-methyl-7-(trifluoromethyl) indoline-2, the 3-diketone
According to by agile this base people such as (Lisowski) ( Referring toOrganic chemistry magazine (J.Org.Chem.), 2000,65:4193) described program.Make intermediate 79 (1.12g, 3.28mmol) and tetrakis triphenylphosphine palladium (190mg 0.16mmol) is dissolved in the 100mL glycol dimethyl ether in the 500mL round-bottomed flask.By with vacuum communicating, purify this solution three times with the nitrogen backfill subsequently.(390mg 6.6mmol), adds sodium bicarbonate (0.55g, the 6.6mmol) solution in 100mL water, and repeat evacuation/nitrogen backfill program once more subsequently to add methyl-boron-dihydroxide.Heated mixt and analyze monitoring product outward appearance/initial substance by LC-MS and disappear under reflux temperature.1.5 after hour, add 190mg (0.16mmol) palladium catalyst again and reactant heated whole night under reflux temperature.Remove organic solvent and make the residue aqueous mixture between the 2M of each 100mL hydrochloric acid and ethyl acetate, divide molten.Again with the ethyl acetate extraction water layer and with the organic layer of salt water washing merging, via anhydrous magnesium sulfate drying, filter and concentrate generating crude product, by flash chromatography on silica gel method (the 0-6% ethyl acetate in the methylene dichloride) come the described crude product of purifying with generation have enough purity intermediate 80 (described product contain have an appointment 20% take off iodine by product 7-(trifluoromethyl) isatin). 1H?NMR(400MHz，DMSO-d 6)δ3.33(s，3H)，7.62(s，1H)，7.68(s，1H)，11.35(s，1H)。
Preparation intermediate 81:N-(4-chloro-2-(trifluoromethyl) phenyl)-2-(oxyimino) ethanamide
Use by the triumphant Charles Bell of L. people such as (L.Kuyper) ( Referring toMedical chemistry magazine (J.Med.Chem.) 2001,44:4339) reported method.In the 1L round-bottomed flask, anhydrous sodium sulphate (85g) is dissolved in the 230mL boiling water.Add 4-chloro-2-(trifluoromethyl) aniline (6.5g, 33mmol) solution in 50mL 1M hydrochloric acid, 2mL concentrated hydrochloric acid and 30mL ethanol of heat.Add 60mL ethanol again.Add Chloral Hydrate (6.6g, 40mmol), add subsequently oxammonium hydrochloride in the 30mL water (7.6g, 0.11mol).Heated mixt and interpolation ethanol dissolve once more up to aniline under reflux temperature.Continue heating 3 hours.Utilize the flask that is communicated with atmosphere, the reacting by heating mixture whole night under reflux temperature.Make reaction mixture be cooled to 0 ℃ and by filter collecting the pale precipitation thing.This throw out that contains a large amount of sodium sulfate is dissolved in the 300mL water, at room temperature stirred 1 hour, filter, be dissolved in the 200mL water, stirred 30 minutes, filtration and dry to generate pale powder (intermediate 81,2.65g, 30% productive rate) under vacuum. 1H?NMR(400MHz，DMSO-d 6)δ7.66(s，1H)，7.76-7.86(m，3H)，9.63(s，1H)，12.44(s，1H)。
Preparation intermediate 82:5-chloro-7-(trifluoromethyl) indoline-2, the 3-diketone
According to M. bandit agate people such as (M.Kollmar) ( Referring toOrganic synthesis (Org.Synth.), " 2-amino-3-fluorobenzoic acid (2-Amino-3-fluorobenzoic acid) ") program.In the 50mL erlenmeyer flask, under agitation the 4mL vitriol oil is heated to 70 ℃.Progressively add intermediate 81, make temperature maintenance simultaneously below 90 ℃.90 ℃ of following reheat reaction mixtures 1 hour.Make it be cooled fast to 20 ℃, pour in the mixture of the 35mL frozen water of vigorous stirring and 7mL ethyl acetate.After all ice have all melted, separate each layer, and use the ethyl acetate extraction water layer again.Organic layer with salt water washing merging, via anhydrous magnesium sulfate drying, filter and concentrate, come the described solid of purifying to have the intermediate 82 (0.633g, 42% productive rate) of enough purity with generation by flash chromatography on silica gel method (the 0-6% ethyl acetate in the methylene dichloride) to generate the brownish black solid. 1H?NMR(400MHz，DMSO-d 6)67.87(d，J＝2.0Hz，1H)，7.94(d，J＝2.0Hz，1H)，11.58(s，1H)。
Preparation intermediate 83:5-phenyl-7-(trifluoromethyl) indoline-2, the 3-diketone
According to above synthetic described program for intermediate 80, tetrakis triphenylphosphine palladium (339mg, 0.29mmol) and sodium bicarbonate (0.98g 12mmol) exists and to make intermediate 77 down (2.0g, 5.9mmol) (0.79g 6.5mmol) reacts with phenyl-boron dihydroxide.After 1 hour, LC-MS analyzes and shows the initial substance completely dissolve.After 2 hours, make reaction mixture cool to room temperature and as indicated above the processing to generate pure products (intermediate 83,0.98g, 57% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ7.41(t，J＝7.2Hz，1H)，7.49(t，J＝7.6Hz，2H)，7.75(ddd，J＝7.6，2.2，1.9Hz，2H)，8.06(d，J＝4.6Hz，2H)，11.56(s，1H)。
Preparation intermediate 84:4-(trifluoromethyl) the phenylcarbamic acid tert-butyl ester
In the 250mL round-bottomed flask, make 4-(trifluoromethyl) aniline (7.7mL, 10g, 62mmol) and tert-Butyl dicarbonate (13.6g, 62.1mmol) be dissolved in the 60mL anhydrous tetrahydro furan and under reflux temperature the heating whole night.Behind the cool to room temperature, remove solvent and resistates is dissolved in the 250mL ethyl acetate.With three parts of 125mL 0.5M citric acids and this solution of 125mL salt water washing,, filter and concentrate via anhydrous magnesium sulfate drying.Come purifying to be white in color the solid crude product by flash chromatography on silica gel method (the 2-20% ethyl acetate in the hexane) to generate fine hair shape white solid (intermediate 84,14.4g, 89% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.49(s，9H)，7.59-7.63(m，2H)，7.64-7.68(m，2H)，9.79(s，1H)。
Preparation intermediate 85:2-(2-tert-butoxycarbonyl amino)-5-(trifluoromethyl) phenyl)-2-oxo ethyl acetate
According to by He Wawasen people such as (Hewawasam) ( Referring toTetrahedron wall bulletin (Tetrahedron Lett.) 1994,35:7303) described program.(9.62g 36.8mmol) puts into the 500mL round-bottomed flask, and with the hexane azeotropic, and drying is whole night under vacuum with intermediate 84.Under nitrogen atmosphere, add the 55mL anhydrous tetrahydro furan and make solution be cooled to-78 ℃ (dry ice/acetone) subsequently by syringe.Via syringe with quick drop form add s-butyl lithium cyclohexane solution (1.4M, 63mL, 88mmol).Make reaction mixture be warmed up to-40 ℃ (dry ice/acetonitrile) and continue 2 hours.After making the gained mixture be cooled to-78 ℃, by syringe whole apace part add diethyl oxalate (6.0mL, 6.5g, 49mmol).Under-78 ℃, reaction mixture was stirred 45 minutes, and with 15mL 1M hydrochloric acid stopped reaction.Add hydrochloric acid again and be acid up to mixture, and with two parts of extracted with diethyl ether gained mixtures.Ether layer with the salt water washing merges via anhydrous magnesium sulfate drying, filters, concentrate and by flash chromatography on silica gel method (the 1-10% ethyl acetate in the hexane) purifying to generate the faint yellow oily thing of viscosity (intermediate 85,4.46g, 34% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.28(t，J＝7.2Hz，3H)，1.44(s，9H)，4.28(q，J＝7.2Hz，2H)，7.69(d，J＝8.3Hz，1H)，7.91(d，J＝2.0Hz，1H)，7.92-7.96(m，1H)，10.18(s，1H)。
Preparation intermediate 86:5-(trifluoromethyl) indoline-2, the 3-diketone
According to by He Wawasen people such as (Hewawasam) ( Referring toTetrahedron wall bulletin (Tetrahedron Lett.), 1994,35:7303) described program.Intermediate 85 is dissolved in the tetrahydrofuran (THF) and 3M hydrochloric acid of each 90mL, and heated solution is converted into product fully up to LC-MS and t.l.c. analysis (5% ethyl acetate in the methylene dichloride) demonstration whole night under reflux temperature.After removing organic solvent, product is precipitated out from solution immediately.By solid collected by filtration, wash with water, and dry to generate fine hair shape bright yellow crystal (intermediate 86,2.22g, 85% productive rate) under vacuum. 1HNMR(400MHz，DMSO-d 6)δ7.08(d，J＝8.3Hz，1H)，7.81(s，1H)，7.90-7.95(m，1H)，11.39(s，1H)。
Preparation intermediate 87:7-iodo-5-(trifluoromethyl) indoline-2, the 3-diketone
According to above for intermediate 77 described programs, at trifluoromethayl sulfonic acid (2.7mL, 4.6g, 31mmol) make intermediate 86 (2.22g under the existence, 10.3mmol) and two (pyridine) iodine (I) tetrafluoride boron (5.75g, 15.5mmol) reaction is the pure products (intermediate 87,3.27g, 93% productive rate) of bright yellow powder with generation. 1H?NMR(400MHz，DMSO-d 6)δ7.80(s，1H)，8.28(dd，J＝1.8，0.8Hz，1H)，11.38(s，1H)。
Preparation intermediate 88:7-methyl-5-(trifluoromethyl) indoline-2, the 3-diketone
According to above for intermediate 80 described programs, tetrakis triphenylphosphine palladium (127mg, 0.110mmol) and sodium bicarbonate (0.37g 4.4mmol) exists and to make intermediate 87 down (0.746g, 2.19mmol) (0.26g 4.4mmol) reacts with methyl-boron-dihydroxide.Under reflux temperature the reacting by heating mixture whole night, add subsequently palladium catalyst other aliquots containig (127mg, 0.110mmol), and under reflux temperature reheat reaction mixture 5 hours.As indicated above it is handled and purifying, have the product (intermediate 88,0.259g, 52% productive rate) of enough purity with generation. 1H?NMR(400MHz，DMSO-d 6)δ2.27(s，3H)，7.63(s，1H)，7.82(s，1H)，11.44(s，1H)。
Preparation intermediate 89:5-ethyl-7-(trifluoromethyl) indoline-2, the 3-diketone
According to above for intermediate 80 described programs, at dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (176mg, 0.215mmol) and cesium carbonate (4.20g, 12.9mmol) make intermediate 77 (1.47g under existing, 4.30mmol) with the tetrahydrofuran solution of boron triethyl (1.0M, 8.6mL, 8.6mmol) reaction.Flash chromatography on silica gel method (the 0-6% ethyl acetate in the methylene dichloride) produces the product (intermediate 89,0.417g, 40% productive rate) with enough purity. 1H?NMR(400MHz，DMSO-d 6)δ1.17(t，J＝7.6Hz，3H)，2.65(q，J＝7.6Hz，2H)，7.66(s，1H)，7.69(s，1H)，11.35(s，1H)。
Preparation intermediate 90:7-ethyl-5-(trifluoromethyl) indoline-2, the 3-diketone
According to above for intermediate 80 described programs, at dichloro [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) methylene dichloride adducts (192mg, 0.235mmol) and cesium carbonate (4.58g, 14.1mmol) make intermediate 87 (1.60g under existing, 4.70mmol) with the tetrahydrofuran solution of boron triethyl (1.0M, 9.4mL, 9.4mmol) reaction.Come the purifying crude product to generate yellowish-orange solid (intermediate 90,0.439g, 38% productive rate) by flash chromatography on silica gel method (the 1-10% ethyl acetate in the methylene dichloride). 1H?NMR(400MHz，DMSO-d 6)δ1.16(t，J＝7.5Hz，3H)，2.64(q，J＝7.6Hz，2H)，7.65(s，1H)，7.80(d，J＝0.8Hz，1H)，11.45(s，1H)。
Preparation intermediate 91:8-phenyl-5-(trifluoromethyl) indoline-2, the 3-diketone
According to above for intermediate 80 described programs, tetrakis triphenylphosphine palladium (272mg, 0.235mmol) and sodium bicarbonate (0.79g 9.4mmol) exists and to make intermediate 87 down (1.60g, 4.70mmol) (0.63g 5.2mmol) reacts with phenyl-boron dihydroxide.Come the purifying crude product to generate yellowish-orange solid (0.585g, 43% productive rate) by flash chromatography on silica gel method (the 0-6% ethyl acetate in the methylene dichloride): 1H NMR (400MHz, DMSO-d 6) δ 7.45-7.55 (m, 5H), 7.84 (dd, J=11.2,1.4Hz, 2H), 11.28 (s, 1H).
Preparation intermediate 92:1-(1-phenycyclopropyl)-2-hydroxyl ethyl ketone
For intermediate 78 described programs, (20g, 0.12mol) (90mL, 150g is 1.2mol) with three (trimethylsiloxy group) ethene (70mL, 62g, 0.21mol) reaction with thionyl chloride successively to make 1-phenyl cyclopropane-carboxylic acid according to above.Come the purifying crude product to generate almost colourless oily matter (intermediate 92,9.44g, 44% productive rate) by flash chromatography on silica gel method (the 2-20% ethyl acetate in the hexane). 1H?NMR(400MHz，CDCl 3)δ1.31(q，J＝3.7Hz，2H)，1.74(q，J＝3.6Hz，2H)，3.18(t，J＝4.9Hz，1H)，4.06(d，J＝5.1Hz，2H)，7.33-7.38(m，5H)。
Preparation intermediate 93:5-bromo-7-(trifluoromethyl) indoline-2, the 3-diketone
Make intermediate 6 (4.56g, 21.2mmol) be dissolved in the 45mL acetate in the 250mL round-bottomed flask and add bromine (5.4mL, 17g, 0.11mol).At room temperature stirred solution whole night.LC-MS analyzes demonstration and is not converted into product fully.Add again bromine (1.1mL, 3.4g, 21mmol) and restir gained mixture 5 hours.Pour into reaction mixture on the trash ice and it is left standstill up to ice-out.By filtration collecting precipitation thing, the water repetitive scrubbing, and dry to generate meticulous bright orange crystal (intermediate 93,5.12g, 82% productive rate) under vacuum. 1H?NMR(400MHz，DMSO-d 6)δ7.96(d，J＝2.0Hz，1H)，8.04(d，J＝2.0Hz，1H)，11.59(s，1H)。
Preparation intermediate 94:2, two (trifluoromethyl) phenylcarbamic acid tert-butyl esters of 4-
In the 100mL 2 neck round-bottomed flasks that are equipped with condenser, make 2, (5.33g 23.3mmol) is dissolved in the 25mL anhydrous tetrahydro furan two (trifluoromethyl) aniline of 4-.Make solution be cooled to 0 ℃ and add sodium hydride in the mineral oil (1.03g, 60wt%, 0.615g NaH, 25.6mmol).Under 0 ℃, stirred the mixture 30 minutes and add tert-Butyl dicarbonate (10.2g, 46.6mmol).At room temperature stirred reaction mixture 1.5 hours and under reflux temperature the heating whole night.Flash chromatography on silica gel method (the 0-4% ethyl acetate in the hexane) produces pure substance (intermediate 94,3.14g, 41% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.46(s，9H)，7.82(d，J＝8.6Hz，1H)，7.99(s，1H)，8.04(dd，J＝8.5，1.6Hz，1H)，8.98(s，1H)。
Preparation intermediate 95:2-(2-(tert-butoxycarbonyl amino)-3, two (trifluoromethyl) phenyl of 5-)-2-oxo ethyl acetate
According to above for intermediate 85 described programs, make intermediate 94 (3.14g, 9.54mmol) with the cyclohexane solution of s-butyl lithium (1.4M, 16.3mL, 22.9mmol) and diethyl oxalate (1.6mL, 1.7g 11mmol) react.Flash chromatography on silica gel method (the 2-20% ethyl acetate in the hexane) produces pure products (intermediate 95,1.91g, 47% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.29(t，J＝7.1Hz，3H)，1.40(s，9H)，4.32(q，J＝7.1Hz，2H)，8.26(s，1H)，8.43(s，1H)，9.69(s，1H)。
Preparation intermediate 96:5, two (trifluoromethyl) indolines-2 of 7-, 3-diketone
According to above for intermediate 86 described programs: (1.83g 4.27mmol), produces bright yellow powder (intermediate 96,0.931g, 77% productive rate) to hydrolysis intermediate 95. 1HNMR(400MHz，DMSO-d 6)δ8.11(s，1H)，8.16(s，1H)，11.86(s，1H)。
Preparation intermediate 97:(1-phenyl-cyclopropyl)-acetate
According to by Weir spy people such as (Wilt) ( Referring toOrganic chemistry magazine (J.Org.Chem.), 1966,31:3018) described program prepares intermediate 97.
Preparation intermediate 98:1-hydroxyl-3-(1-phenyl-cyclopropyl)-third-2-ketone
Come synthetic mesophase thing 98 according to the program that is used for intermediate 51, wherein make (1-phenyl-cyclopropyl)-acetate (intermediate 97,0.3g, 1.70mmol) and 3mL thionyl chloride and 1,1, (1.2mL, 3.40mmol) reaction is the required product (0.2g, 62% productive rate) of colorless oil to 2-three (trimethylsiloxy group) ethane with generation. 1H?NMR(400MHz，CDCl 3)δ0.91-0.97(m，2H)，1.21-1.28(m，2H)，2.63(s，2H)，4.42(s，2H)，7.23-7.39(m，5H)。
Preparation intermediate 99:1-phenmethyl-cyclopropane-carboxylic acid
According to by Ba Sha people such as (Bartha) ( Referring toRevue Roumaine de Chimie (Romanian The Chemicals), 1986,31:519) described program prepares intermediate 99.(5.67g is 86.6mmol) with cuprous chloride (8.6g, 86.6mmol) mixture in the 100mL ether and heating 30 minutes under reflux temperature under nitrogen to stir zinc powder.Add fast 2-phenmethyl-methyl acrylate (3.85g, 21.9mmol) and methylene iodide (2.3mL, 28.1mmol wherein are dissolved with 100mg iodine).Stirred reaction mixture is 6 hours under reflux temperature.At room temperature add saturated ammonium chloride (30mL).Remove solid via filtration.Separate organic layer and with two parts of 30mL extracted with diethyl ether water layers.The organic layer that concentrates merging makes described oily matter saponification to generate faint yellow oily thing with the potassium hydroxide in the methyl alcohol.Via column chromatography (silica gel, ethyl acetate: hexane=1: 5) come purifying intermediate 99.Acquisition is the intermediate 99 (0.9g, 23% productive rate) of faint yellow oily thing. 1H?NMR(400MHz，CDCl 3)δ0.85-0.90(m，2H)，1.33-1.37(m，2H)，3.62(s，2H)，7.14-7.34(m，5H)。
Preparation intermediate 100:1-(1-phenmethyl-cyclopropyl)-2-hydroxyl-ethyl ketone
Come synthetic mesophase thing 100 according to the program that is used for intermediate 51, wherein make 1-phenmethyl-cyclopropane-carboxylic acid (intermediate 99,0.9g, 5.1mmol) and 5mL thionyl chloride and 1,1, (3.7mL, 10.2mmol) reaction is the required product (0.8g, 82% productive rate) of colorless oil to 2-three (trimethylsiloxy group) ethane with generation. 1H?NMR(400MHz，CDCl 3)δ0.87-0.90(m，2H)，1.34-1.38(m，2H)，3.55(s，2H)，3.70-3.71(s，2H)，7.15-7.31(m，5H)。
Preparation intermediate 101:1-(2-(trifluoromethyl) phenyl) cyclopropane formonitrile HCN
According to by Yue Enqike people such as (Jonczyk) ( Referring toInternational organic preparation procedure (Org.Prep.Proc.Int.), 1995,27 (3): 355-359) described program prepares this compound.In the 25mL round-bottomed flask that is equipped with condenser, add 2-(2-(trifluoromethyl) phenyl) acetonitrile (1.0g, 5.4mmol, 1.0 equivalents), 1-bromo-2-monochloroethane (0.67mL, 8.1mmol, 1.5 equivalent) and chlorination triethylbenzene ammonium methyl (0.024g, 0.11mmol, 0.02 equivalent).With gained mixture heating up to 50 ℃ and dropwise add sodium hydroxide (6.0 equivalents are dissolved in the 1.0mL water for 1.3g, 32.4mmol).Under 50 ℃, stirred the mixture cool to room temperature and pouring in the 50mL water 16 hours.With three parts of these suspension of 25mL dichloromethane extraction, and the organic layer that merges with three parts of 50mL 1.2N HCl solution, three parts of 50mL water and the washing of 50mL saturated nacl aqueous solution.Via the dried over mgso organic layer, filter and remove in a vacuum solvent.Come the thick material of purifying to be the required product (intermediate 101,0.92g, 81% productive rate) of faint yellow oily thing with generation by silica gel chromatography (Biotage Flash 40,10% ethyl acetate/hexane). 1H?NMR(400MHz，CDCl 3)δ1.30-1.52(m，2H)，1.65-1.86(m，2H)，7.42-7.52(m，1H)，7.53-7.60(m，2H)，7.71(d，J＝7.58Hz，1H)。
Preparation intermediate 102:1-(2-(trifluoromethyl) phenyl) cyclopropane-carboxylic acid
In the 50mL round-bottomed flask that is equipped with condenser, add intermediate 101 (1-(2-(trifluoromethyl) phenyl) cyclopropane formonitrile HCN, 0.92g, 4.4mmol, 1.0 equivalents) and 20mL 4.0N LiOH solution.Heating this suspension and stirring 3 days under reflux temperature.Make gained mixture cool to room temperature and pour among the 250mL 1.2N HCl.Wash the organic layer that merges with three parts of these suspension of 75mL ethyl acetate extraction and with three parts of 200mL water and 200mL saturated nacl aqueous solution.Via the dried over mgso organic layer, filter and remove in a vacuum solvent.The acquisition required product of solid (intermediate 102,0.87g, 86% productive rate) that is white in color. 1H?NMR(400MHz，CDCl 3)δ1.18-1.45(m，2H)，1.58-1.94(m，J＝81.09Hz，2H)，7.31-7.42(m，1H)，7.43-7.54(m，2H)，7.64(d，J＝7.83Hz，1H)。
Preparation intermediate 103:2-chloro-1-(1-(2-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone
In the 50mL round-bottomed flask that is equipped with condenser, add intermediate 102 (1-(2-(trifluoromethyl) cyclopropane-carboxylic acid, 0.83g, 3.61mmol, 1.0 equivalents) and 25mL thionyl chloride.Heating gained solution and stirring 4 hours under reflux temperature.Behind the cool to room temperature, remove all volatile matters immediately in a vacuum.Make the gained brown oil be dissolved among the 10mLTHF again and dropwise add in the ethereal solution of the 100mL diazomethane that is cooled to 0 ℃.Make this mixture slowly be warmed up to room temperature and stirred 12 hours.Make solution cooling get back to 0 ℃ and make HCl gas therein bubbling reach 3 minutes.Trash ice added in the mixture and continue stirred 15 minutes.Separate each layer and with two parts of 50mL extracted with diethyl ether water layers.The organic layer that merges with three parts of 100mL saturated sodium bicarbonate solutions, three parts of 100mL water and the washing of 100mL saturated nacl aqueous solution.Via dried over mgso solution, filter and remove in a vacuum solvent is colorless oil with generation intermediate 103 (0.339g, 36% productive rate). 1H?NMR(400MHz，CDCl 3)δ0.85-1.83(m，4H)，3.98(d，J＝6.32Hz，2H)，7.42-7.55(m，1H)，7.56-7.65(m，2H)，7.74(d，J＝7.58Hz，1H)。
Preparation intermediate 104: acetate 2-oxo-2-(1-(2-(trifluoromethyl) phenyl) cyclopropyl) ethyl ester
In 5mL microwave reaction bottle, add intermediate 103 (2-chloro-1-(1-(2-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.339g, 1.35mmol, 1.0 equivalents) and 2mL acetone.In gained solution, add acetate (0.1mL, 1.76mmol, 1.3 equivalents) and triethylamine (0.25mL, 1.76mmol, 1.3 equivalents).Seal described bottle and in microwave reactor, be heated to 150 ℃ and continue 30 minutes.Gained suspension poured in the 50mL water and with three parts of 25mL ethyl acetate extractions.Organic layer with three parts of 75mL water and 75mL saturated nacl aqueous solution washing merging.Via the dried over mgso organic layer, filter and remove solvent to generate brown oil.Come this oily matter of purifying with the generation required product of solid (intermediate 104,0.235g, 64% productive rate) that is white in color by silica gel chromatography (Biotage Flash 40,0-10% ethyl acetate/hexane). 1H?NMR(400MHz，CDCl 3)δ1.30-1.42(m，J＝12.88Hz，2H)，1.44-1.63(m，2H)，2.10(s，3H)，4.23-4.42(m，1H)，4.53-4.72(m，1H)，7.45-7.53(m，1H)，7.56-7.67(m，2H)，7.73(d，J＝8.59Hz，1H)。
Preparation intermediate 105:5-isopropyl indole quinoline-2, the 3-diketone
By being used for the method for intermediate 63, use the 4-isopropyl aniline as initial substance, with 75% productive rate synthetic mesophase thing 105. 1H?NMR(400MHz，DMSO-d 6)δ1.17(d，J＝6.8Hz，6H)，2.81-2.93(m，1H)，6.84(d，J＝8.1Hz，1H)，7.38(d，J＝1.8Hz，1H)，7.49(dd，J＝8.2，1.9Hz，1H)，10.94(br?s，1H)。
Prepare exemplary compound
Compound 1:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethoxy) quinoline-4-formic acid
(1.00g 4.32mmol) is dissolved in 1mL ethanol and the 3.4mL 10M sodium hydroxide and heating gained mixture 20 minutes under reflux temperature to make intermediate 13.Via syringe dropwise add intermediate 55 in 7mL ethanol solution and heating gained mixture whole night.Make its cool to room temperature and under reduced pressure remove ethanol.The dilute with water resistates is acidified to pH 1 and uses ethyl acetate extraction by slow interpolation 1M hydrochloric acid.The ethyl acetate layer that concentrates merging comes the described material of purifying to produce dark matter by preparation HPLC (water/acetonitrile and 0.1% triethylamine).Make the triethyl ammonium salt of purifying be dissolved in 20% acetonitrile solution and use the concentrated hydrochloric acid acidifying.The pure products that is pale powder that collection is settled out from solution is to generate compound 1 (83mg, 4.5% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.35-1.39(m，2H)，1.49-1.54(m，2H)，7.16(d，J＝8.6Hz，2H)，7.28(d，J＝8.6Hz，2H)，7.57(d，1H)，7.62(t，1H)，8.69(d，J＝7.3Hz，1H)。
Compound 2:2-(1-(4-chloro-phenyl-) cyclopropyl)-8-ethyl-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 1, (0.38g is 2.2mmol) with intermediate 55 (0.71g, 2.8mmol) reaction to make intermediate 63.The product of acidifying purifying does not produce solid sediment and with the aqueous acetonitrile mixture of ethyl acetate extraction.Concentrated ethyl acetate layer that merges and freeze-drying are to generate fine hair shape bright yellow solid (compound 2,140mg, 18% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.32(t，J＝7.5Hz，3H)，1.36-1.42(m，2H)，1.50-1.61(m，2H)，3.23(q，J＝7.5Hz，2H)，7.19(d，2H)，7.29(d，J＝8.6Hz，2H)，7.45(d，1H)，7.51(t，1H)，8.35(d，J＝8.3Hz，1H)。
Compound 3:8-sec-butyl-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 2, use intermediate 65 (0.44g, 2.2mmol) and intermediate 55 (0.71g 2.8mmol) prepares as initial substance and is fine hair shape bright yellow solid compound 3 (81mg, 9.5% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ0.82(t，J＝7.3Hz，3H)，1.32(d，J＝7.1Hz，3H)，1.35-1.44(m，2H)，1.46-1.60(m，2H)，1.63-1.85(m，2H)，4.10(q，1H)，7.19(d，J＝8.6Hz，2H)，7.29(d，J＝8.6Hz，2H)，7.44(d，J＝7.1Hz，1H)，7.55(t，1H)，8.32(d，J＝8.3Hz，1H)。
The compound 4:8-tertiary butyl-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 2, use intermediate 67 (0.44g, 2.2mmol) and intermediate 55 (0.71g 2.8mmol) prepares as initial substance and is fine hair shape light brown solid compound 4 (59mg, 3.4% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.36-1.42(m，2H)，1.48-1.54(m，2H)，1.65(s，9H)，7.22(d，2H)，7.30(d，2H)，7.45-7.54(m，2H)，8.26(dd，J＝7.5，2.2Hz，1H)。
Compound 5:8-chloro-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 2, use 7-chloro-indole quinoline-2,3-diketone (senior synthetic (Advanced Synthesis), 0.39g, 2.2mmol) and intermediate 55 (0.71g, 2.8mmol) prepare as initial substance and to be fine hair shape bright yellow solid compound 5 (93mg, 11% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.32-1.38(m，2H)，1.51-1.58(m，2H)，7.15(d，J＝8.6Hz，2H)，7.27(d，J＝8.3Hz，2H)，7.47(t，1H)，7.64(d，J＝7.6Hz，1H)，8.87(d，J＝8.3Hz，1H)。
Compound 6:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-phenylquinoline-4-formic acid
According to for the described program of the preparation of compound 1, use intermediate 11 (7-Phenylindole quinoline-2, the 3-diketone, 0.48g, 2.2mmol) (0.71g 2.8mmol) prepares compound 6 as initial substance with intermediate 55.It is black to remove the Pd that is stayed by Suzuki coupling (Suzuki coupling) step to filter the refrigerative reaction mixture, with the 1M hcl acidifying and use ethyl acetate extraction.The acetonitrile solution of triethyl ammonium salt that comes purifying crude product and acidifying purifying by preparation HPLC as indicated above to be generating the bright yellow powder, collects described powder and dry to generate compound 5 (249mg, 28% productive rate) under vacuum by filtering. 1H?NMR(400MHz，DMSO-d 6)δ1.26-1.31(m，2H)，1.46-1.52(m，2H)，7.06(d，J＝8.6Hz，2H)，7.24(d，J＝8.6Hz，2H)，7.39(t，J＝7.3Hz，1H)，7.48(t，J＝7.6Hz，2H)，7.58-7.70(m，4H)，8.54(dd，J＝8.6，1.3Hz，1H)。
Compound 7:2-(1-(4-chloro-phenyl-) cyclopropyl)-8-fluoro-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 1, (495mg, 3.00mmol) (0.99g 3.9mmol) prepares compound 7 as initial substance with intermediate 55 to use intermediate 69.With 2M hcl acidifying refrigerative reaction mixture and use ethyl acetate extraction.Come the purifying crude product by preparation HPLC (water/acetonitrile and 0.1% triethylamine).Merge the elution part contain compound 7, concentrate removing acetonitrile, cooling and use the concentrated hydrochloric acid acidifying in ice-water bath.By filter collecting white depositions, wash with water and dry to generate compound 7 (300mg, 28% productive rate) under vacuum. 1H?NMR(400MHz，DMSO-d 6)δ1.35-1.45(m，2H)，1.45-1.55(m，2H)，7.16(dt，J＝9.0，2.8Hz，2H)，7.28(dt，J＝9.1，2.5Hz，2H)，7.39(ddd，1H)，7.57(dt，J＝8.2，5.6Hz，1H)，8.39(d，J＝8.8Hz，1H)。
Compound 8:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 1, make indoline-2, (Aldrich company (Aldrich), 441mg is 3.00mmol) with intermediate 55 (0.99g, 3.9mmol) reaction for the 3-diketone.To generate the bright yellow throw out, collect described throw out with concentrated hydrochloric acid acidifying refrigerative reaction mixture, wash with water by filtering, under vacuum dry and from acetonitrile/ethanol recrystallize.Acquisition is the compound 8 (272mg, 27% productive rate) of meticulous bright yellow crystalline material. 1H?NMR(400MHz，DMSO-d 6)δ1.37-1.44(m，2H)，1.50-1.57(m，2H)，7.19(dt，2H)，7.29(dt，J＝9.1，2.7Hz，2H)，7.56-7.67(m，2H)，7.99-8.04(m，1H)，8.72(s，1H)。
Compound 9:8-bromo-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 1, (678mg is 3.00mmol) with intermediate 55 (0.99g, 3.9mmol) reaction to make intermediate 71.With glacial acetic acid the refrigerative reaction mixture is acidified to pH 4 and uses ethyl acetate extraction.The ethyl acetate layer that concentrates merging comes the described product of purifying to generate crude product by preparation HPLC (water/acetonitrile and 0.1% triethylamine).Merge the elution part contain compound 9, concentrate, with the concentrated hydrochloric acid acidifying and use ethyl acetate extraction to remove acetonitrile.The ethyl acetate layer that freeze-drying merges is to generate bright yellow powder (compound 9,303mg, 24% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.36-1.47(m，2H)，1.54-1.65(m，2H)，7.17(dt，J＝9.0，2.8Hz，2H)，7.29(dt，J＝9.1，2.5Hz，2H)，7.49(dd，J＝8.6，7.3Hz，1H)，7.95(dd，J＝7.5，1.1Hz，1H)，8.58(dd，J＝8.6，1.3Hz，1H)。
Compound 10:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6,8-dimethyl quinoline-4-formic acid
According to for the described program of the preparation of compound 1, make 5,7-dimethyl indole quinoline-2, (Lancaster company (Lancaster), 526mg is 3.00mmol) with intermediate 55 (0.99g, 3.9mmol) reaction for the 3-diketone.To generate the bright yellow throw out, collect described throw out with concentrated hydrochloric acid acidifying refrigerative reaction mixture by filtering, dry and by preparation HPLC (water/acetonitrile and 0.1% triethylamine) purifying under vacuum.Merge the elution part contain compound 10, concentrate, with the concentrated hydrochloric acid acidifying and use ethyl acetate extraction to remove acetonitrile.The ethyl acetate layer that freeze-drying merges is to generate bright yellow powder (compound 10,298mg, 27% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.33-1.42(m，2H)，1.47-1.57(m，2H)，2.44(s，3H)，2.69(s，3H)，7.15(dt，J＝9.0，2.8Hz，2H)，7.27(dt，J＝9.1，2.77Hz，2H)，7.30(s，1H)，8.13(s，1H)。
Compound 11:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-toluquinoline-4-formic acid
According to for the described program of the preparation of compound 10, use intermediate 73 (7-skatole quinoline-2,3-diketone, 313mg, 1.94mmol) and intermediate 55 (0.64g 2.5mmol) prepares the compound 11 (247mg, 36% productive rate) that is yellow powder as initial substance. 1H?NMR(400MHz，DMSO-d 6)δ1.36-1.43(m，2H)，1.50-1.58(m，2H)，2.74(s，3H)，7.16(dt，J＝9.0，2.8Hz，2H)，7.28(dt，J＝9.0，2.5Hz，2H)，7.43-7.51(m，2H)，8.36(dd，J＝8.2，1.4Hz，1H)。
Compound 12:2-(1-(4-chloro-phenyl-) cyclopropyl)-7-ethyl-3-hydroxyquinoline-4-formic acid
According to the program that is used for compound 10, use 4-ethylindole quinoline-2,3-diketone (senior synthetic (AdvancedSynthesis), 924mg, 5.27mmol) and intermediate 55 prepare the compound 12 (5.3mg, 0.3% productive rate) that is fine hair shape yellow solid as initial substance. 1H?NMR(400MHz，DMSO-d 6)δ1.28(t，J＝7.6Hz，3H)，1.35-1.42(m，2H)，1.48-1.54(m，2H)，2.78(q，J＝7.5Hz，2H)，7.20(d，2H)，7.28(d，2H)，7.49(d，J＝9.9Hz，1H)，7.80(s，1H)，8.73(s，1H)。
Compound 13:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-7-toluquinoline-4-formic acid
According to for the described program of the preparation of compound 1, make intermediate 75 and 76 mixture (3.34,20.1mmol) with intermediate 55 (6.80g, 26.9mmol) reaction.To generate the bright yellow throw out, collect described throw out with 1M hcl acidifying refrigerative reaction mixture, wash with water by filtering, under vacuum dry and with ebullient acetonitrile/ethanol wet-milling with generation compound 14 (1.64g, 22% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.36-1.42(m，2H)，1.49-1.54(m，2H)，2.48(s，3H)，7.16-7.23(m，2H)，7.26-7.32(m，2H)，7.46(d，J＝9.9Hz，1H)，7.80(s，1H)，8.69(s，1H)。
Compound 14:8-ethyl-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
Handle intermediate 63 (0.38g, ethanolic soln 2.2mmol) and heated mixt under reflux temperature with 10.0N aqueous sodium hydroxide solution (9.0 equivalent).Added intermediate 8 (0.6g, ethanolic soln 2.8mmol) through 60 minutes in this solution of clockwise.With gained mixture restir 3 hours under reflux temperature.Behind the cool to room temperature, under reduced pressure remove ethanol immediately.Mixture is acidified to pH 1 and pours in the water with 1M HCl.The thick solid that comes purifying to obtain by reversed-phase HPLC (water/acetonitrile/0.1% triethylamine).Merge the elution part contain compound 14 and freeze-drying to generate required product (0.146g, 20% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.32(t，J＝7.5Hz，3H)，1.34-1.41(m，2H)，1.46-1.54(m，2H)，3.23(q，J＝7.3Hz，2H)，7.09-7.29(m，5H)，7.39-7.55(m，2H)，8.37(dd，J＝8.5，1.39Hz，1H)。
Compound 15:8-sec-butyl-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.373g, 1.8mmol) (0.5g, 2.3mmol) reaction is to generate compound 15 (0.116g, 18% productive rate) with intermediate 8 to make intermediate 65. 1H?NMR(400MHz，DMSO-d 6)δ0.82(t，J＝7.3Hz，3H)，1.32(d，J＝6.8Hz，3H)，1.34-1.41(m，2H)，1.42-1.55(m，2H)，1.61-1.90(m，2H)，3.06-3.13(m，1H)，7.07-7.27(m，5H)，7.41(d，J＝7.1Hz，1H)，7.47-7.60(m，1H)，8.39(d，J＝8.3Hz，1H)。
Compound 16:7-chloro-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 6-chloro-indole quinoline-2, (0.182g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 16 (0.06g, 19% productive rate) with intermediate 55 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.28-1.44(m，2H)，1.44-1.58(m，2H)，7.17(d，J＝8.6Hz，2H)，7.28(d，J＝8.3Hz，2H)，7.62(dd，J＝9.2，2.2Hz，1H)，8.01(d，J＝2.3Hz，1H)，8.75(d，J＝9.4Hz，1H)。
Compound 17:2-(1-(4-chloro-phenyl-) cyclopropyl)-6-fluoro-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-fluoro indole quinoline-2, (0.165g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 17 (0.1g, 28% productive rate) with intermediate 55 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.30-1.41(m，2H)，1.43-1.55(m，2H)，7.14-7.21(m，2H)，7.23-7.31(m，2H)，7.37-7.50(m，1H)，8.02(dd，J＝9.1，6.1Hz，1H)，8.58(d，J＝12.6Hz，1H)。
Compound 18:6-bromo-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-bromo indole quinoline-2, (0.226g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 18 (0.12g, 29% productive rate) with intermediate 55 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.29-1.38(m，2H)，1.43-1.54(m，2H)，7.11-7.22(m，2H)，7.22-7.32(m，2H)，7.60(dd，J＝8.84，2.27Hz，1H)，7.86(d，J＝8.84Hz，1H)，9.17(d，J＝2.02Hz，1H)
Compound 19:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-toluquinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-skatole quinoline-2, (0.161g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 19 (0.10g, 28% productive rate) with intermediate 55 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.34-1.44(m，2H)，1.46-1，61(m，2H)，2.50(s，3H)，7.19(d，J＝8.3Hz，2H)，7.24-7.34(m，2H)，7.34-7.48(m，1H)，7.89(d，J＝8.3Hz，1H)，8.57(br?s，1H)。
Compound 20:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-methoxy quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-methoxyl group indoline-2, (0.177g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 20 (0.07g, 19% productive rate) with intermediate 55 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.39(s，2H)，1.43-1.57(m，2H)，3.87(s，3H)，7.06-7.37(m，5H)，7.92(d，J＝9.1Hz，1H)，8.35(br?s，1H)。
Compound 21:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-(trifluoromethoxy) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-(trifluoromethoxy) indoline-2, (0.231g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 22 (0.148g, 35% productive rate) with intermediate 55 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.28-1.41(m，2H)，1.41-1.60(m，2H)，7.09-7.22(m，2H)，7.22-7.34(m，2H)，7.43(d，J＝11.4Hz，1H)，8.02(d，J＝9.1Hz，1H)，8.99(s，1H)。
Compound 22:6-chloro-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-chloro-indole quinoline-2, (0.182g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 22 (0.101g, 27% productive rate) with intermediate 55 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.30-1.43(m，2H)，1.43-1.58(m，2H)，7.07-7.22(m，2H)，7.23-7.37(m，2H)，7.57(dd，J＝8.8，2.3Hz，1H)，7.98(d，J＝8.8Hz，1H)，8.85(d，J＝1.8Hz，1H)。
Compound 23:2-(1-(4-chloro-phenyl-) cyclopropyl)-3,6-dihydroxyl quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-oxyindole quinoline-2, (0.163g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 23 (0.09g, 25% productive rate) with intermediate 55 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.40(s，2H)，1.47-1.56(m，2H)，7.13(dd，J＝9.0，2.7Hz，1H)，7.16-7.25(m，2H)，7.25-7.33(m，2H)，7.84-7.92(m，1H)，8.24(br?s，1H)，10.20(br?s，1H)。
Compound 24:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-(trifluoromethyl) indoline-2, (0.215g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 24 (0.041g, 10% productive rate) with intermediate 55 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.28-1.45(m，2H)，1.47-1.67(m，2H)，7.10-7.23(m，2H)，7.24-7.38(m，2H)，7.79(s，1H)，8.16(d，J＝8.8Hz，1H)，9.26(s，1H)。
Compound 25:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxy-6-isopropylquinoline-4-4-formic acid
According to for the described program of the preparation of compound 14, make intermediate 105 (5-isopropyl indole quinoline-2, the 3-diketone, 0.189g, 1mmol) (0.316g, 1.25mmol) reaction is to generate compound 25 (0.06g, 16% productive rate) with intermediate 55. 1H?NMR(400MHz，DMSO-d 6)δ1.28(d，J＝6.8Hz，6H)，1.40(s，2H)，1.46-1.58(m，2H)，2.86-3.17(m，1H)，7.11-7.22(m，2H)，7.22-7.32(m，2H)，7.53(dd，J＝8.6，1.77Hz，1H)，7.95(d，J＝8.6Hz，1H)，8.62(br?s，1H)。
Compound 26:7-chloro-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 6-chloro-indole quinoline-2, (0.156g, 0.86mmol) (0.234g, 1.1mmol) reaction is to generate compound 26 (0.07g, 20% productive rate) with intermediate 8 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.31-1.43(m，2H)，1.44-1.55(m，2H)，6.99-7.32(m，5H)，7.61(dd，J＝9.5，2.2Hz，1H)，8.01(d，J＝2.5Hz，1H)，8.78(d，J＝9.4Hz，1H)。
Compound 27:6-ethyl-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-ethylindole quinoline-2, (0.1g, 0.57mmol) (0.156g, 0.72mmol) reaction is to generate compound 27 (0.066g, 18% productive rate) with intermediate 8 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.26(t，J＝1.6Hz，3H)，1.50(s，2H)，2.66-2.93(m，2H)，7.06-7.33(m，5H)，7.48(dd，J＝8.6，1.52Hz，1H)，7.94(d，J＝8.6Hz，1H)，8.58(s，1H)。
Compound 28:7-ethyl-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 6-ethylindole quinoline-2, (0.175g, 1mmol) (0.273g, 1.25mmol) reaction is to generate compound 28 (0.07g, 21% productive rate) with intermediate 8 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.28(t，J＝7.5Hz，3H)，1.35-1.44(m，2H)，1.47-1.53(m，2H)，2.79(q，J＝7.5Hz，2H)，7.07-7.31(m，5H)，7.50(d，J＝1.0Hz，1H)，7.83(s，1H)，8.69(s，1H)。
Compound 29:3-hydroxyl-2-(1-phenycyclopropyl)-6-(trifluoromethoxy) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-(trifluoromethoxy) indoline-2, (0.231g, 1mmol) (0.273g, 1.25mmol) reaction is to generate compound 29 (0.11g, 26% productive rate) with intermediate 8 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.27-1.43(m，2H)，1.42-1.54(m，2H)，7.01-7.31(m，5H)，7.46(dd，J＝9.1，2.1Hz，1H)，8.05(d，J＝9.1Hz，1H)，8.95(s，1H)。
Compound 30:6-chloro-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-chloro-indole quinoline-2, (0.182g, 1mmol) (0.273g, 1.25mmol) reaction is to generate compound 30 (0.09g, 27% productive rate) with intermediate 8 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.25-1.44(m，2H)，1.43-1.58(m，2H)，6.98-7.32(m，5H)，7.57(dd，J＝8.8，2.3Hz，1H)，8.00(d，J＝8.8Hz，1H)，8.86(s，1H)。
Compound 31:3-hydroxyl-8-methyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make intermediate 73 (7-skatole quinoline-2, the 3-diketone, 0.161g, 1mmol) (0.273g, 1.25mmol) reaction is to generate compound 31 (0.064g, 20% productive rate) with intermediate 8. 1H?NMR(400MHz，MeOD)δ1.32-1.37(m，2H)，1.49-1.61(m，2H)，2.78(s，3H)，7.04-7.16(m，1H)，7.15-7.31(m，4H)，7.31-7.48(m，2H)，8.74(dd，J＝7.6，2.3Hz，1H)。
Compound 32:3-hydroxyl-2-(1-phenycyclopropyl)-6-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-(trifluoromethyl) indoline-2, (0.215g, 1mmol) (0.273g, 1.25mmol) reaction is to generate compound 32 (0.041g, 11% productive rate) with intermediate 8 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.25-1.36(m，2H)，1.38-1.53(m，2H)，6.94-7.32(m，4H)，7.59(dd，J＝8.6，2.0Hz，1H)，8.02(d，J＝8.3Hz，1H)，8.87(br?s，1H)，9.72(s，1H)。
Compound 33:3-hydroxyl-6-methyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make 5-skatole quinoline-2, (0.161g, 1mmol) (0.273g, 1.25mmol) reaction is to generate compound 33 (0.13g, 40% productive rate) with intermediate 8 for the 3-diketone. 1H?NMR(400MHz，DMSO-d 6)δ1.39-1.42(m，2H)，1.48-1.52(m，2H)，2.50(s，3H)，7.07-7.36(m，5H)，7.44(dd，J＝8.6，1.8Hz，1H)，7.93(d，J＝8.1Hz，1H)，8.60(s，1H)。
Compound 34:3-hydroxyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make intermediate 6 (7-Trifluoromethyl-1 H-indoles-2, the 3-diketone, 0.40g, 1.86mmol) and intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 0.45g 2.05mmol) reaction is the compound 34 (0.20g, 29% productive rate) of faint yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δ1.68(dd，J＝7.0，4.7Hz，2H)，7.46(dd，J＝7.0，4.7Hz，2H)，7.51-7.59(m，2H)，7.66(dd，J＝8.6，7.3Hz，2H)，7.87(dd，J＝8.4，1.5Hz，1H)，8.14(d，J＝9.0Hz，1H)，9.91(d，J＝9.0Hz，1H)。
Compound 35:3-hydroxyl-2-(1-phenycyclopropyl)-8-(thiene-3-yl-) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make intermediate 54 (7-(thiene-3-yl-) indoline-2, the 3-diketone, 0.30g, 1.30mmol) and intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 0.31g 1.40mmol) reaction is the compound 35 (0.12g, 24% productive rate) of faint yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δ1.52(dd，J＝7.1，4.0Hz，2H)，1.73-1.78(dd，J＝7.1，4.0Hz，2H)，7.25-7.34(m，1H)，7.35-7.43(m，1H)，7.43-7.50(m，1H)，7.62-7.72(m，2H)，7.83-7.87(m，2H)，7.88-7.93(m，2H)，8.13-8.18(m，1H)，9.41-9.47(m，1H)。
Compound 36:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.16g is 0.80mmol) with intermediate 55 (acetate 2-(1-(4-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester, 0.22g to make intermediate 3,0.88mmol) reaction is the compound 36 (33.3mg, 10.6% productive rate) of yellow solid with generation. 1H?NMR(400MHz，DMSO-D 6)δ1.22-1.32(m，2H)，1.40-1.48(m，2H)，1.72-1.91(m，4H)，2.75-2.87(m，2H)，3.17-3.26(m，2H)，7.13-7.18(m，3H)，7.24(d，J＝8.1Hz，2H)，7.37-7.48(m，1H)，8.85-9.08(m，2H)。
Compound 37:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(thiene-3-yl-) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.19g is 0.83mmol) with intermediate 55 (acetate 2-(1-(4-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester, 0.23g to make intermediate 54,0.91mmol) reaction is the compound 37 (110mg, 31.4% productive rate) of yellow solid with generation. 1H?NMR(400MHz，CDCl 3)δ1.62(dd，J＝6.8，4.7Hz，2H)，2.38-2.65(m，2H)，7.16(d，J＝8.9Hz，2H)，7.22(d，J＝8.9Hz，2H)，7.37(dd，J＝5.1，3.1Hz，1H)，7.49(dd，J＝8.6，7.2Hz，1H)，7.66(dd，J＝7.2，1.5Hz，1H)，7.70(dd，J＝5.1，1.2Hz，1H)，7.97(dd，J＝3.1，1.2Hz，1H)，9.27(dd，J＝8.6，1.5Hz，1H)。
Compound 38:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make intermediate 6 (7-(trifluoromethyl) indoline-2, the 3-diketone, 0.41g, 1.91mmol) and intermediate 55 (acetate 2-(1-(4-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester, 0.53g 2.10mmol) reaction is the compound 38 (190mg, 24.4% productive rate) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δ1.58(dd，J＝7.5，4.6Hz，2H)，1.82(dd，J＝7.5，4.6Hz，2H)，7.44(d，J＝8.7Hz，2H)，7.53(d，J＝8.7Hz，2H)，7.87(dd，J＝8.7，7.6Hz，1H)，8.14(d，J＝7.6Hz，1H)，9.29(d，J＝8.7Hz，1H)。
Compound 39:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-isopropyl quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make intermediate 5 (7-isopropyl indole quinoline-2, the 3-diketone, 0.16g, 0.83mmol) and intermediate 55 (acetate 2-(1-(4-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester, 0.19g 0.91mmol) reaction is the compound 39 (134mg, 42.3% productive rate) of yellow solid with generation. 1H NMR (400MHz, CDCl 3) δ 1.33 (dd, J=6.9,4.6Hz, 2H), 1.37 (d, J=6.9Hz, 6H), 1.60 (dd, J=6.9,4.6Hz, 2H), 4.37 (septet, J=6.9Hz, 1H), 7.15 (d, J=8.6Hz, 2H), 7.24 (d, J=8.6Hz, 2H), 7.33 (dd, J=7.3,1.2Hz, 1H), 7.41 (dd, J=8.5,7.3Hz, 1H), 9.00 (dd, J=8.5Hz, 1H).
Compound 40:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-7,8-dimethyl quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make intermediate 4 (6,7-dimethyl indole quinoline-2, the 3-diketone, 70mg is 0.39mmol) with intermediate 55 (acetate 2-(1-(4-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester, 108mg, 0.43mmol) reaction is the compound 40 (42.5mg, 29.7% productive rate) of yellow solid with generation. 1H?NMR(400MHz，CDCl 3)δ1.34(dd，J＝7.2，4.0Hz，2H)，1.62(dd，J＝7.2，4.0Hz，2H)，2.43-2.47(s，3H)，2.74-2.78(s，3H)，7.15(d，J＝8.5Hz，2H)，7.20(d，J＝8.5Hz，2H)，7.30(d，J＝9.0Hz，1H)，8.97(d，J＝9.0Hz，1H)。
Compound 41:2-(1-(4-chloro-phenyl-) cyclopropyl)-8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyquinoline -4-formic acid
According to for the described program of the preparation of compound 14, (7-(1,1 to make intermediate 16,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl) indoline-2, the 3-diketone, 240mg is 0.77mmol) with intermediate 55 (acetate 2-(1-(4-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester, 212mg, 0.85mmol) reaction is with the generation solid compound 41 (28.5mg, 7.3% productive rate) that is white in color. 1H?NMR(400MHz，MeOH-D 4)δ1.67-1.74(m，4H)，7.49(dd，J＝9.7Hz，2H)，7.57(d，J＝9.7Hz，2H)，7.92(dd，J＝8.4，8.4Hz，1H)，8.12(d，J＝8.4Hz，1H)，9.27(d，J＝8.4Hz，1H)。
Compound 42:3-hydroxyl-2-(1-phenycyclopropyl)-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (5.0mL, 48.6mmol, 9.0 equivalent) make intermediate 3 (6,7,8 under the existence, 9-tetrahydrochysene-1H-benzo [g] indoles-2, the 3-diketone, 1.34g, 5.4mmol, 1.0 equivalent) with intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 1.51g, 6.93mmol, 1.3 equivalents) and reaction.Acquisition is the compound 42 (0.2799g, 14% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.29-1.39(m，2H)，1.44-1.56(m，2H)，1.74-1.91(m，4H)，2.84(t，J＝5.43Hz，2H)，3.26(t，J＝6.06Hz，2H)，7.10-7.17(m，3H)，7.18-7.23(m，2H)，7.28(d，J＝8.59Hz，1H)，8.36(d，J＝9.35Hz，1H)。
Compound 43:3-hydroxyl-7,8-dimethyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, under existing, 10.0N aqueous sodium hydroxide solution (5.1mL, 51.4mmol, 9.0 equivalents) makes intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 1.65g, 7.4mmol, 1.3 equivalents) and intermediate 4 (6,7-dimethyl indole quinoline-2, the 3-diketone, 1.0g, 5.71mmol, 1.0 equivalents) and reaction.Acquisition is the compound 43 (0.732g, 39% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.29-1.41(m，2H)，1.46-1.62(m，2H)，2.42(s，3H)，2.71(s，3H)，7.10-7.16(m，3H)，7.18-7.26(m，2H)，7.41(d，J＝8.59Hz，1H)，8.28(d，J＝8.84Hz，1H)。
Compound 44:3-hydroxyl-8-sec.-propyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (4.8mL, 47.6mmol, 9.0 equivalents) and make intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 0.80g under existing, 3.6mmol, 0.7 equivalent) with intermediate 5 (7-isopropyl indole quinoline-2,3-diketone, 1.0g, 5.29mmol, 1.0 equivalents) and reaction.Acquisition is the compound 44 (0.724g, 40% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.35(d，J＝7.07Hz，6H)，1.36-1.40(m，2H)，1.43-1.53(m，2H)，3.53-5.07(h，J＝8.59Hz，1H)，7.00-7.30(m，5H)，7.40-7.48(m，1H)，7.48-7.59(m，1H)，8.37(d，J＝8.59Hz，1H)。
Compound 45:3-hydroxyl-8-phenyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.47mL, 4.2mmol, 9.0 equivalents) and make intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 0.133g under existing, 0.61mmol, 1.3 equivalent) with intermediate 11 (7-Phenylindole quinoline-2,3-diketone, 0.105g, 0.47mmol, 1.0 equivalents) and reaction.Acquisition is the compound 45 (0.032g, 18% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.22-1.32(m，2H)，1.37-1.50(m，2H)，6.98-7.06(m，1H)，7.07-7.13(m，1H)，7.14-7.24(m，2H)，7.33-7.42(m，1H)，7.48(t，J＝7.45Hz，2H)，7.53-7.59(m，1H)，7.60-7.70(m，4H)，8.64(d，J＝7.83Hz，1H)。
Compound 46:3-hydroxyl-2-(1-phenycyclopropyl)-8-(trifluoromethoxy) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (1.17mL, 11.68mmol, 9.0 equivalents) and make intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 0.368g under existing, 1.69mmol, 1.3 equivalent) with intermediate 13 (7-(trifluoromethoxy) indoline-2,3-diketone, 0.300g, 1.30mmol, 1.0 equivalents) and reaction.Acquisition is the compound 46 (0.076g, 15% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.30-1.39(m，2H)，1.42-1.53(m，2H)，6.99-7.18(m，3H)，7.18-7.27(m，2H)，7.46-7.73(m，2H)，8.74(d，J＝7.58Hz，1H)。
Compound 47:8-chloro-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (2.48mL, 24.78mmol, 9.0 equivalent) make intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 0.780g, 3.58mmol under the existence, 1.3 equivalent) with 7-chloro-indole quinoline-2,3-diketone (0.500g, 2.75mmol, 1.0 equivalents) reaction.Acquisition is the compound 47 (0.308g, 33% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.33-1.40(m，2H)，1.48-1.59(m，2H)，6.88-7.36(m，5H)，7.53(t，J＝8.59Hz，1H)，7.72(dd，J＝7.45，1.14Hz，1H)，8.64(d，J＝8.59Hz，1H)。
Compound 48:6-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-first Acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (1.4mL, 14.4mmol, 9.0 (5-(1,1,1 equivalent) to make intermediate 15 under the existence, 3,3,3-hexafluoro-2-hydroxyl third-2-yl) indoline-2, the 3-diketone, 0.50g, 1.6mmol, 1.0 equivalent) with intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 0.383g, 1.76mmol, 1.1 equivalents) and reaction.Acquisition is the compound 48 (0.103g, 14% productive rate) of yellow powder. 1HNMR(400MHz，DMSO-d 6)δ1.35-1.42(m，2H)，1.46-1.54(m，2H)，7.01-7.30(m，5H)，7.73-7.86(m，1H)，8.10(d，J＝8.84Hz，1H)，8.91(s，1H)，9.34(s，1H)。
Compound 49:8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-first Acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (16.22mL, 162.0mmol, 9.0 (7-(1,1,1 equivalent) to make intermediate 16 under the existence, 3,3,3-hexafluoro-2-hydroxyl third-2-yl) indoline-2, the 3-diketone, 5.64g, 18.02mmol, 1.0 equivalent) with intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 5.11g, 23.42mmol, 1.3 equivalents) and reaction.Acquisition is the compound 49 (2.52g, 30% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.33-1.40(m，2H)，1.40-1.49(m，2H)，7.13-7.30(m，5H)，7.65-7.71(m，1H)，7.72-7.79(m，1H)，9.06(d，J＝8.34Hz，1H)。
Compound 50:3-hydroxyl-2-(1-(4-p-methoxy-phenyl) cyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.5mL, 5.4mmol, 9.0 equivalents) and make intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone under existing, 0.100g, 0.45mmol, 1.0 equivalents) and intermediate 18 (acetate 2-(1-(4-p-methoxy-phenyl) cyclopropyl)-2-oxo ethyl ester, 0.144g, 0.59mmol, 1.3 equivalents) and reaction.Acquisition is the compound 50 (0.041g, 17% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.18-1.32(m，2H)，1.37-1.50(m，2H)，3.68(s，3H)，6.80(d，J＝9.09Hz，2H)，7.17(d，J＝8.84Hz，2H)，7.66(dd，J＝8.59，6.82Hz，2H)，7.91(d，J＝6.82Hz，1H)，9.00(d，J＝8.59Hz，1H)。
Compound 51:3-hydroxyl-2-(1-(4-p-methoxy-phenyl) cyclopropyl)-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (1.4mL, 14.1mmol, 9.0 equivalent) make intermediate 18 (acetate 2-(1-(4-p-methoxy-phenyl) cyclopropyl)-2-oxo ethyl ester, 0.500g, 2.04mmol under the existence, 1.3 equivalent) with intermediate 3 (6,7,8,9-tetrahydrochysene-1H-benzo [g] indoles-2, the 3-diketone, 0.396g, 1.57mmol, 1.0 equivalents) and reaction.Acquisition is the compound 51 (0.057g, 9.2% productive rate) of yellow powder. 1HNMR(400MHz，DMSO-d 6)δ1.19-1.30(m，2H)，1.39-1.47(m，4H)，1.75-1.96(m，4H)，2.84(t，J＝5.94Hz，2H)，3.27(t，J＝6.06Hz，2H)，3.68(s，3H)，6.78(d，J＝8.59Hz，2H)，7.14(d，J＝8.59Hz，2H)，7.28(d，J＝8.84Hz，1H)，8.27(d，J＝8.59Hz，1H)。
Compound 52:3-hydroxyl-8-(trifluoromethyl)-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.4mL, 4.23mmol, 9.0 equivalents) and make intermediate 21 (2-hydroxyl-1-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.149g under existing, 0.6mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.101g, 0.47mmol, 1.0 equivalents) and reaction.Acquisition is the compound 52 (0.086g, 33% productive rate) of yellow powder. 1H?NMR(400MHz，CDCl 3)δ1.39-1.51(m，2H)，1.57-1.65(m，2H)，7.34(d，J＝8.08Hz，2H)，7.60(d，J＝8.34Hz，2H)，7.65-7.78(m，1H)，7.95(d，J＝7.33Hz，1H)，8.99(d，J＝8.59Hz，1H)。
Compound 53:2-(1-(4-bromophenyl) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.2mL, 2.13mmol, 9.0 equivalents) and make intermediate 25 (acetate 2-(1-(4-bromophenyl) cyclopropyl)-2-oxo ethyl ester, 0.091g under existing, 0.31mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.051g, 0.24mmol, 1.0 equivalents) and reaction.Acquisition is the compound 53 (0.033g, 24% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.28-1.38(m，2H)，1.45-1.54(m，2H)，7.12(d，J＝8.59Hz，2H)，7.41(d，J＝8.59Hz，2H)，7.63(t，J＝8.59Hz，1H)，7.86(d，J＝7.33Hz，1H)，9.18(d，J＝8.59Hz，1H)。
Compound 54:2-(1-(3-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.84mL, 8.4mmol, 9.0 equivalents) and make intermediate 28 (1-(1-(3-chloro-phenyl-) cyclopropyl)-2-hydroxyl ethyl ketone, 0.255g under existing, 1.21mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.200g, 0.93mmol, 1.0 equivalents) and reaction.Acquisition is the compound 54 (0.058g, 15% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.32-1.42(m，2H)，1.44-1.54(m，2H)，6.95-7.37(m，4H)，7.63(t，J＝7.96Hz，1H)，7.86(d，J＝7.33Hz，1H)，9.19(d，J＝8.59Hz，1H)。
Compound 55:2-(1-(2-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.84mL, 8.4mmol, 9.0 equivalents) and make intermediate 32 (acetate 2-(1-(2-chloro-phenyl-) cyclopropyl)-2-oxo ethyl ester, 0.306g under existing, 1.21mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.200g, 0.93mmol, 1.0 equivalents) and reaction.Acquisition is the compound 55 (0.029g, 8% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.14-1.23(m，2H)，1.77-1.89(m，2H)，7.14-7.22(m，1H)，7.23-7.33(m，2H)，7.38-7.50(m，1H)，7.61(d，J＝7.07Hz，1H)，7.72(dd，J＝7.71，1.64Hz，1H)，9.61(d，J＝8.08Hz，1H)。
Compound 56:3-hydroxyl-2-(1-(4-(trifluoromethoxy) phenyl) cyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.84mL, 8.4mmol, 9.0 equivalents) and make intermediate 35 (2-hydroxyl-1-(1-(4-(trifluoromethoxy) phenyl) cyclopropyl) ethyl ketone, 0.315g under existing, 0.93mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.200g, 0.93mmol, 1.0 equivalents) and reaction.Acquisition is the compound 56 (0.142g, 33% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.33-1.44(m，2H)，1.47-1.58(m，2H)，7.19-7.25(m，2H)，7.25-7.31(m，2H)，7.60-7.76(m，1H)，7.92(d，J＝7.58Hz，1H)，9.03(d，J＝8.34Hz，1H)。
Compound 57:3-hydroxyl-8-(trifluoromethyl)-2-(1-(3-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (1.9mL, 19.5mmol, 9.0 equivalents) and make intermediate 38 (2-hydroxyl-1-(1-(3-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.687g under existing, 2.82mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.466g, 2.17mmol, 1.0 equivalents) and reaction.Acquisition is the compound 57 (0.369g, 30% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.39-1.48(m，2H)，1.52-1.62(m，2H)，7.37-7.58(m，4H)，7.67(t，J＝8.34Hz，1H)，7.92(d，J＝7.07Hz，1H)，9.05(d，J＝8.34Hz，1H)。
Compound 58:2-(1-(4-chloro-phenyl-) cyclobutyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N sodium hydroxide (1.3mL, 12.6mmol, 9.0 equivalents) and make intermediate 42 (acetate 2-(1-(4-chloro-phenyl-) cyclobutyl)-2-oxo ethyl ester, 0.476g under existing, 1.80mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.300g, 1.40mmol, 1.0 equivalents) and reaction.The be white in color compound 58 (0.293g, 50% productive rate) of powder of acquisition. 1H?NMR(400MHz，DMSO-d 6)δ1.73-2.06(m，2H)，2.55-2.78(m，2H)，2.95-3.25(m，2H)，7.35(q，J＝8.34Hz，4H)，7.69(t，J＝7.96Hz，1H)，7.97(d，J＝7.58Hz，1H)，8.92(d，J＝8.59Hz，1H)。
Compound 59:3-hydroxyl-2-(1-(thiene-3-yl-) cyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N sodium hydroxide (0.24mL, 2.36mmol, 9.0 equivalents) and make intermediate 45 (2-hydroxyl-1-(1-(thiene-3-yl-) cyclopropyl) ethyl ketone, 0.062g under existing, 0.34mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.056g, 0.26mmol, 1.0 equivalents) and reaction.Acquisition is the compound 59 (0.033g, 26% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.27-1.36(m，2H)，1.39-1.55(m，2H)，6.86(dd，J＝4.93，1.39Hz，1H)，6.98(dd，J＝2.91，1.39Hz，1H)，7.36(dd，J＝5.05，3.03Hz，1H)，7.58-7.69(m，1H)，7.87(d，J＝7.07Hz，1H)，9.15(d，J＝8.59Hz，1H)。
Compound 60:3-hydroxyl-2-(1-(thiophene-2-yl) cyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N sodium hydroxide (1.5mL, 14.72mmol, 9.0 equivalents) and make intermediate 48 (2-hydroxyl-1-(1-(thiophene-2-yl) cyclopropyl) ethyl ketone, 0.387g under existing, 2.13mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.352g, 1.64mmol, 1.0 equivalents) and reaction.Acquisition is the compound 60 (0.251g, 31% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.33-1.43(m，2H)，1.49-1.63(m，2H)，6.82-6.85(m，1H)，6.86-6.89(m，1H)，7.24(dd，J＝5.05，1.26Hz，1H)，7.61-7.74(m，1H)，7.92(d，J＝7.07Hz，1H)，9.01(d，J＝8.59Hz，1H)。
Compound 61:2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N sodium hydroxide (2.1mL, 21.1mmol, 9.0 equivalents) and make intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.590g under existing, 3.05mmol, 1.3 equivalent) with intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone, 0.504g, 2.34mmol, 1.0 equivalents) and reaction.Acquisition is the compound 61 (0.132g, 14% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.24-1.35(m，2H)，1.40-1.51(m，2H)，6.93-7.12(m，2H)，7.17-7.34(m，2H)，7.62(t，J＝8.08Hz，1H)，7.86(d，J＝7.33Hz，1H)，9.17(d，J＝9.60Hz，1H)。
Compound 62:2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-isopropyl quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N sodium hydroxide (0.8mL, 7.95mmol, 9.0 equivalents) and make intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.223g under existing, 1.15mmol, 1.3 equivalent) with intermediate 5 (7-isopropyl indole quinoline-2,3-diketone, 0.167g, 0.88mmol, 1.0 equivalents) and reaction.Acquisition is the compound 62 (0.126g, 39% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.28-1.39(m，8H)，1.43-1.53(m，2H)，4.15-4.34(m，1H)，6.94-7.12(m，2H)，7.19-7.29(m，2H)，7.41-7.47(，d，J＝8.08Hz，1H)，7.48-7.56(t，J＝8.08Hz，1H)，8.40(d，J＝8.08Hz，1H)。
Compound 63:3-hydroxyl-8-(trifluoromethyl)-2-(1-(2-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (5.6mL, 5.7mmol, 9.0 equivalents) and make intermediate 6 (7-(trifluoromethyl) indoline-2,3-diketone under existing, 0.136g, 0.63mmol, 1.0 equivalents) and intermediate 104 (acetate 2-oxo-2-(1-(2-(trifluoromethyl) phenyl) cyclopropyl) ethyl ester, 0.235g, 0.82mmol, 1.3 equivalents) and reaction.Acquisition is the compound 63 (0.043g, 15% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.32-1.45(m，2H)，1.92-2.06(m，2H)，7.44(t，J＝7.71Hz，1H)，7.51-7.68(m，3H)，7.80(d，J＝7.07Hz，1H)，7.85(d，J＝7.83Hz，1H)，9.08(d，J＝8.59Hz，1H)。
Compound 64:3-hydroxyl-6,8-dimethyl-2-(1-phenycyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (2.5mL, 25.7mmol, 9.0 equivalents) and make 5,7-dimethyl indole quinoline-2 under existing, 3-diketone (0.50g, 2.86mmol, 1.0 equivalents) and intermediate 8 (acetate 2-oxo-2-(1-phenycyclopropyl) ethyl ester, 0.81g, 3.71mmol, 1.3 equivalents) and reaction.Acquisition is the compound 64 (0.492g, 52% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.28-1.39(m，2H)，1.45-1.59(m，2H)，2.44(s，3H)，2.69(s，3H)，7.05-7.17(m，3H)，7.17-7.25(m，2H)，7.29(s，1H)，8.17(s，1H)。
Compound 65:8-ethyl-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) and make intermediate 63 (7-ethylindole quinoline-2,3-diketone under existing, 0.139g, 0.8mmol, 1.0 equivalents) and intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 65 (0.055g, 20% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.24-1.38(m，5H)，1.42-1.54(m，2H)，3.22(q，J＝7.33Hz，2H)，6.92-7.12(m，2H)，7.19-7.31(m，2H)，7.39-7.42(m，1H)，7.44-7.50(m，1H)，8.45(d，J＝8.34Hz，1H)。
Compound 66:7-ethyl-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalent) make 6-ethylindole quinoline-2,3-diketone (0.139g, 0.8mmol under the existence, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 66 (0.050g, 18% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.28(t，J＝7.58Hz，3H)，1.36(t，J＝5.05Hz，2H)，1.43-1.54(m，2H)，2.78(q，J＝7.66Hz，2H)，7.05(t，J＝8.84Hz，2H)，7.27(dd，J＝8.34，5.56Hz，2H)，7.48(d，J＝8.84Hz，1H)，7.79(s，1H)，8.80(s，1H)。
Compound 67:6-chloro-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalent) make 5-chloro-indole quinoline-2,3-diketone (0.145g, 0.8mmol under the existence, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 67 (0.130g, 45% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.32(dd，J＝8.00，4.00Hz，4H)，1.45(dd，J＝8.00，4.00Hz，4H)，7.04(dd，J＝8.84，5.56Hz，2H)，7.24(dd，J＝8.84，5.56Hz，2H)，7.49(dd，J＝8.84，2.53Hz，1H)，7.93(d，J＝8.84Hz，1H)，9.01(s，1H)。
Compound 68:7-chloro-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalent) make 6-chloro-indole quinoline-2,3-diketone (0.145g, 0.8mmol under the existence, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 68 (0.109g, 38% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.33(dd，J＝8.00，4.00Hz，2H)，1.45(dd，J＝8.00，4.00Hz，2H)，6.97-7.10(m，2H)，7.15-7.34(m，2H)，7.57(dd，J＝9.09，2.27Hz，1H)，7.97(d，J＝2.53Hz，1H)，8.87(d，J＝9.09Hz，1H)。
Compound 69:2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-6,8-dimethyl quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) and make 5,7-dimethyl indole quinoline-2 under existing, 3-diketone (0.140g, 0.8mmol, 1.0 equivalents) and intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 69 (0.147g, 52% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.32(dd，J＝8.00，4.00Hz，2H)，1.49(dd，J＝8.00，4.00Hz，2H)，2.43(s，3H)，2.69(s，3H)，7.04(t，J＝8.59Hz，2H)，7.20(dd，J＝8.59，5.56Hz，2H)，7.28(s，1H)，8.18(s，1H)。
Compound 70:6-ethyl-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalent) make 5-ethylindole quinoline-2,3-diketone (0.100g, 0.6mmol under the existence, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.8 equivalents) and reaction.Acquisition is the compound 70 (0.099g, 47% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.25(t，J＝7.58Hz，3H)，1.33-1.42(m，2H)，1.44-1.54(m，2H)，2.78(q，J＝7.49Hz，2H)，7.05(t，J＝8.84Hz，2H)，7.26(dd，J＝8.21，5.68Hz，2H)，7.46(dd，J＝8.72，1.64Hz，1H)，7.93(d，J＝8.59Hz，1H)，8.65(s，1H)。
Compound 71:2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-(thiene-3-yl-) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) and make intermediate 54 (7-(thiene-3-yl-) indoline-2,3-diketone under existing, 0.183g, 0.8mmol, 1.0 equivalents) and intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 71 (0.157g, 48% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.32(dd，J＝4.00，2.00Hz，2H)，1.52(dd，J＝4.00，2.00Hz，2H)，7.57-7.66(m，2H)，7.72(d，J＝5.05Hz，1H)，7.78(d，J＝6.57Hz，1H)，8.08(d，J＝2.27Hz，1H)，8.49(d，J＝8.59Hz，1H)。
Compound 72:6-bromo-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalent) make 5-bromo indole quinoline-2,3-diketone (0.181g, 0.8mmol under the existence, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 72 (0.145g, 45% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.33(dd，J＝4.00，2.00Hz，2H)，1.46(dd，J＝4.00，2.00Hz，2H)，7.04(t，J＝8.84Hz，2H)，7.24(dd，J＝8.72，5.43Hz，2H)，7.63(dd，J＝8.84，2.02Hz，1H)，7.88(d，J＝8.84Hz，1H)，9.10(d，J＝1.26Hz，1H)。
Compound 73:8-chloro-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalent) make 7-chloro-indole quinoline-2,3-diketone (0.145g, 0.8mmol under the existence, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 73 (0.045g, 16% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.34(dd，J＝8.00，4.00Hz，2H)，1.53(dd，J＝8.00，4.00Hz，2H)，7.04(t，J＝8.97Hz，2H)，7.21(dd，J＝8.72，5.43Hz，2H)，7.51(t，J＝8.21Hz，1H)，7.69(d，J＝7.58Hz，1H)，8.69(d，J＝8.59Hz，1H)。
Compound 74:7-bromo-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalent) make 6-bromo indole quinoline-2,3-diketone (0.181g, 0.8mmol under the existence, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 74 (0.142g, 44% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.33(dd，J＝4.00，2.00Hz，2H)，1.45(dd，J＝8.00，4.00Hz，2H)，7.04(t，J＝8.97Hz，2H)，7.24(dd，J＝8.84，5.56Hz，2H)，7.68(dd，J＝9.35，2.27Hz，1H)，8.13(d，J＝2.27Hz，1H)，8.78(d，J＝9.35Hz，1H)。
Compound 75:8-bromo-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) and make intermediate 71 (7-bromo indole quinoline-2,3-diketone under existing, 0.181g, 0.8mmol, 1.0 equivalents) and intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 75 (0.160g, 50% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.33(dd，J＝4.00，2.00Hz，4H)，1.53(dd，J＝8.00，4.00Hz，2H)，7.04(t，J＝8.72Hz，2H)，7.21(dd，J＝8.59，5.56Hz，2H)，7.40(t，J＝8.00Hz，1H)，7.84(dd，J＝7.45，1.14Hz，1H)，8.86(d，J＝8.84Hz，1H)。
Compound 76:2-(1-(4-fluorophenyl) cyclopropyl)-8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyquinoline -4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 (7-(1,1,1 equivalent) to make intermediate 16 under the existence, 3,3,3-hexafluoro-2-hydroxyl third-2-yl) indoline-2, the 3-diketone, 0.250g, 0.8mmol, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 76 (0.152g, 39% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.39(d，J＝4.29Hz，4H)，7.09(t，J＝8.72Hz，2H)，7.29(dd，J＝8.59，5.56Hz，2H)，7.67(t，J＝7.60Hz，1H)，7.70-7.80(m，1H)，9.11(d，J＝8.34Hz，1H)。
Compound 77:2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-phenylquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) and make intermediate 11 (7-Phenylindole quinoline-2,3-diketone under existing, 0.178g, 0.8mmol, 1.0 equivalents) and intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 77 (0.132g, 41% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.25(dd，J＝8.00，4.00Hz，2H)，1.45(dd，J＝8.00，4.00Hz，2H)，7.01(t，J＝8.97Hz，2H)，7.11(dd，J＝8.72，5.43Hz，2H)，7.39(t，J＝7.33Hz，1H)，7.48(t，J＝7.45Hz，2H)，7.55-7.61(m，1H)，7.65(t，J＝7.71Hz，3H)，8.58(dd，J＝8.46，1.14Hz，1H)。
Compound 78:2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-toluquinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) and make intermediate 73 (7-skatole quinoline-2,3-diketone under existing, 0.129g, 0.8mmol, 1.0 equivalents) and intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 78 (0.122g, 45% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.34(dd，J＝4.00，2.00Hz，32H)，1.51(dd，J＝4.00，2.00Hz，2H)，2.73(s，3H)，7.04(t，J＝8.97Hz，2H)，7.22(dd，J＝8.72，5.43Hz，2H)，7.35-7.66(m，2H)，8.41(s，1H)。
Compound 79:2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-6-methoxy quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalent) make 5-methoxyl group indoline-2,3-diketone (0.142g, 0.8mmol under the existence, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 79 (0.053g, 19% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.36(s，2H)，1.47(s，2H)，7.05(t，J＝8.84Hz，2H)，7.22(dd，J＝9.22，2.65Hz，2H)，7.28(dd，J＝7.33，5.05Hz，1H)，7.92(d，J＝9.09Hz，1H)，8.42(s，1H)。
Compound 80:2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalent) make intermediate 3 (6,7,8 under the existence, 9-tetrahydrochysene-1H-benzo [g] indoles-2, the 3-diketone, 0.202g, 0.8mmol, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 80 (0.034g, 11% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.32(dd，J＝4.00，2.00Hz，2H)，1.48(dd，J＝4.00，2.00Hz，2H)，1.73-1.92(m，4H)，2.84(t，J＝5.68Hz，2H)，3.26(t，J＝5.68Hz，2H)，7.04(t，J＝8.84Hz，2H)，7.22(dd，J＝8.72，5.43Hz，2H)，7.28(d，J＝8.84Hz，1H)，8.34(d，J＝8.84Hz，1H)。
Compound 81:2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-7,8-dimethyl quinoline-4-formic acid
According to for the described program of the preparation of compound 14, under existing, 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) makes intermediate 4 (6,7-dimethyl indole quinoline-2, the 3-diketone, 0.140g, 0.8mmol, 1.0 equivalent) with intermediate 51 (1-(1-(4-fluorophenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.200g, 1.03mmol, 1.3 equivalents) and reaction.Acquisition is the compound 81 (0.105g, 37% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.34(dd，J＝4.00，2.00Hz，2H)，1.51(dd，J＝4.00，2.00Hz，2H)，2.42(s，3H)，2.70(s，3H)，7.04(t，J＝8.84Hz，2H)，7.21(dd，J＝8.59，5.56Hz，2H)，7.40(d，J＝8.84Hz，1H)，8.31(d，J＝8.59Hz，1H)。
Compound 82:8-ethyl-2-(1-p-methylphenyl cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, under existing, 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) makes intermediate 63 (7-ethylindole quinoline-2, the 3-diketone, 0.140g, 0.8mmol, 1.0 equivalents) and intermediate 77 (1-(1-(4-aminomethyl phenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.297g, 1.03mmol, 1.3 equivalents, 66% purity) and reaction.Acquisition is the compound 82 (0.129g, 46% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.23-1.36(m，5H)，1.40-1.60(m，2H)，2.22(s，3H)，3.23(q，J＝7.49Hz，2H)，6.89-7.14(m，4H)，7.40-7.44(m，1H)，7.48(t，J＝7.60Hz，1H)，8.40(d，J＝7.33Hz，1H)。
Compound 83:8-methyl-2-(1-p-methylphenyl cyclopropyl)-3-hydroxyquinoline-4-formic acid
According to for the described program of the preparation of compound 14, under existing, 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) makes intermediate 73 (7-skatole quinoline-2, the 3-diketone, 0.129g, 0.8mmol, 1.0 equivalents) and intermediate 77 (1-(1-(4-aminomethyl phenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.297g, 1.03mmol, 1.3 equivalents, 66% purity) and reaction.Acquisition is the compound 83 (0.138g, 52% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.31(dd，J＝8.00，4.00Hz，2H)，1.49(dd，J＝8.00，4.00Hz，2H)，2.22(s，3H)，2.73(s，3H)，6.85-7.13(m，4H)，7.35-7.53(m，2H)，8.39(d，J＝8.34Hz，1H)。
Compound 84:3-hydroxyl-6,8-dimethyl-2-(1-p-methylphenyl cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, under existing, 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) makes 5,7-dimethyl indole quinoline-2,3-diketone (0.140g, 0.8mmol, 1.0 equivalents) and intermediate 77 (1-(1-(4-aminomethyl phenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.297g, 1.03mmol, 1.3 equivalents, 66% purity) and reaction.Acquisition is the compound 84 (0.154g, 55% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.29(dd，J＝4.00，2.00Hz，2H)，1.46(dd，J＝4.00，2.00Hz，2H)，2.22(s，3H)，2.43(s，3H)，2.69(s，3H)，6.83-7.09(m，4H)，7.27(s，1H)，8.20(s，1H)
Compound 85:8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyl-2-(1-p-methylphenyl cyclopropyl) quinoline -4-formic acid
According to for the described program of the preparation of compound 14, at 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 (7-(1,1,1 equivalent) to make intermediate 16 under the existence, 3,3,3-hexafluoro-2-hydroxyl third-2-yl) indoline-2, the 3-diketone, 0.250g, 0.8mmol, 1.0 equivalent) with intermediate 77 (1-(1-(4-aminomethyl phenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.297g, 1.03mmol, 1.3 equivalent, 66% purity) reaction.Acquisition is the compound 85 (0.118g, 30% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.32(d，J＝8.00Hz，2H)，1.37(d，J＝8.00Hz，2H)，2.22(s，3H)，6.96-7.08(m，2H)，7.09-7.15(m，2H)，7.66(t，J＝7.60Hz，1H)，7.72(d，J＝7.60Hz，1H)，9.15(d，J＝7.83Hz，1H)。
Compound 86:3-hydroxyl-8-sec.-propyl-2-(1-p-methylphenyl cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, under existing, 10.0N aqueous sodium hydroxide solution (0.93mL, 9.3mmol, 9.0 equivalents) makes intermediate 5 (7-isopropyl indole quinoline-2, the 3-diketone, 0.1787g, 0.946mmol, 1.0 equivalents) and intermediate 77 (1-(1-(4-aminomethyl phenyl) cyclopropyl)-2-hydroxyl ethyl ketone, 0.297g, 1.03mmol, 1.3 equivalents, 66% purity) and reaction.Acquisition is the compound 86 of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.31(dd，J＝8.00，4.00Hz，2H)，1.34(d，J＝7.07Hz，6H)，1.45(dd，J＝8.00，4.00Hz，2H)，2.22(s，3H)，4.12-4.35(m，1H)，7.02(d，J＝7.90Hz，2H)，7.08(d，J＝7.90Hz，2H)，7.42(d，J＝6.32Hz，1H)，7.50(t，J＝7.63Hz，1H)，8.44(d，J＝8.59Hz，1H)。
Compound 87:8-ethyl-3-hydroxyl-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0M aqueous sodium hydroxide solution (1.026mL, 10.26mmol, 9.0 equivalents) and make intermediate 63 (7-ethylindole quinoline-2,3-diketone under existing, 0.200g, 1.14mmol, 1.0 equivalents) and intermediate 21 (2-hydroxyl-1-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.3624g, 1.484mmol, 1.3 equivalents) and reaction.Acquisition is the compound 87 (0.0613g, 13.4% productive rate) of yellow powder. 1H?NMR(400MHz，CDCl 3)δ1.18-1.29(m，2H)，1.36(t，J＝7.20Hz，3H)，1.40-1.47(m，2H)，3.23-3.33(m，2H)，7.40-7.46(m，3H)，7.46-7.54(m，4H)，8.58(d，J＝8.45Hz?1H)。
Compound 88:3-hydroxyl-8-sec.-propyl-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0M aqueous sodium hydroxide solution (0.85mL, 8.5mmol, 9.0 equivalents) and make intermediate 5 (7-isopropyl indole quinoline-2,3-diketone under existing, 0.1787g, 0.946mmol, 1.0 equivalents) and intermediate 21 (2-hydroxyl-1-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.300g, 1.23mmol, 1.3 equivalents) and reaction.Acquisition is the compound 88 (0.0320g, 8.14% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.34(d，J＝7.07Hz，6H)，1.44-1.51(m，2H)，1.57-1.64(m，2H)，4.20-4.31(m，1H)，7.33(d，J＝8.08Hz，2H)，7.47(d，2H)，7.52-7.62(m，3H)，8.36(d，J＝8.59Hz，1H)。
Compound 89:7-ethyl-3-hydroxyl-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0M aqueous sodium hydroxide solution (0.90mL, 9.00mmol, 9.0 equivalent) make 6-ethylindole quinoline-2,3-diketone (0.1752g, 1.0mmol under the existence, 1.0 equivalent) with intermediate 21 (2-hydroxyl-1-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.3175g, 1.30mmol, 1.3 equivalents) and reaction.Acquisition is the compound 89 (0.0314g, 7.82% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.28(t，J＝7.58Hz，3H)，1.44-1.51(m，2H)，1.55-1.62(m，2H)，2.79(q，J＝7.49Hz，2H)，7.33(d，J＝8.08Hz，2H)，7.50(dd，J＝8.84，1.52Hz，1H)，7.58(d，J＝8.34Hz，2H)，7.81(s，1H)，8.69(d，1H)。
Compound 90:3-hydroxyl-6-(trifluoromethoxy)-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0M aqueous sodium hydroxide solution (0.90mL, 9.0mmol, 9.0 equivalent) make 5-(trifluoromethoxy) indoline-2,3-diketone (0.1893g, 0.819mmol under the existence, 1.0 equivalent) with intermediate 21 (2-hydroxyl-1-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.260g, 1.06mmol, 1.3 equivalents) and reaction.Acquisition is the compound 90 (0.0637g, 17.0% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.43-1.52(m，2H)，1.56-1.64(m，2H)，7.33(d，J＝8.08Hz，2H)，7.50-7.62(m，3H)，8.11(d，J＝9.09Hz，1H)，8.78(d，J＝1.52Hz，1H)。
Compound 91:3-hydroxyl-8-(thiene-3-yl-)-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0M aqueous sodium hydroxide solution (0.90mL, 9.0mmol, 9.0 equivalents) and make intermediate 54 (7-(thiene-3-yl-) indoline-2,3-diketone under existing, 0.18775g, 0.819mmol, 1.0 equivalents) and intermediate 21 (2-hydroxyl-1-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.260g, 1.06mmol, 1.3 equivalents) and reaction.Acquisition is the compound 91 (0.0835g, 22.38% productive rate) of yellow powder. 1HNMR(400MHz，DMSO-d 6)δ1.40-1.47(m，2H)，1.59-1.67(m，2H)，7.56(d，J＝8.34Hz，2H)，7.60-7.65(m，2H)，7.69(dd，J＝5.05，1.26Hz，1H)，7.77(dd，J＝7.33，1.26Hz，1H)，8.04(dd，J＝3.03，1.26Hz，1H)，8.54(d，2H)。
Compound 92:3-hydroxyl-8-phenyl-2-(1-(4-trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, at 10.0M aqueous sodium hydroxide solution (0.13mL, 1.3mmol, 9.0 equivalents) and make intermediate 11 (7-Phenylindole quinoline-2,3-diketone under existing, 0.033g, 0.142mmol, 1.0 equivalents) and intermediate 21 (2-hydroxyl-1-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.045g, 0.184mmol, 1.3 equivalents) and reaction.Acquisition is the compound 92 (0.016g, 25.07% productive rate) of yellow powder. 1H?NMR(400MHz，DMSO-d 6)δ1.32-1.38(m，2H)，1.48-1.59(m，2H)，7.21(d，J＝8.08Hz，2H)，7.38(t，J＝7.45Hz，2H)，7.47(t，J＝7.58Hz，2H)，7.47(t，1H)，7.51-7.56(m，2H)，7.60-7.67(m，3H)，7.71(d，1H)，8.78(d，J＝8.08Hz，1H)。
Compound 93:3-hydroxyl-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl)-7,8,9,10-tetrahydro benzo [h] quinoline-4- Formic acid
According to for the described program of the preparation of compound 14, at 10.0M aqueous sodium hydroxide solution (1.01mL, 10.1mmol, 9.0 equivalent) make intermediate 3 (6,7,8 under the existence, 9-tetrahydrochysene-1H-benzo [g] indoles-2, the 3-diketone, 0.2269g, 1.127mmol, 1.0 equivalent) with intermediate 21 (2-hydroxyl-1-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) ethyl ketone, 0.358g, 1.466mmol, 1.3 equivalents) and reaction.Acquisition is the compound 93 (0.014g, 5% productive rate) of yellow powder. 1HNMR(400MHz，DMSO-d 6)δ1.18-1.27(m，2H)，1.39-1.45(m，2H)，1.49-1.55(m，2H)，1.55-1.62(m，2H)，1.76-1.90(m，4H)，7.25(d，J＝8.84Hz，1H)，7.30(d，J＝7.83Hz，1H)，7.56(d，J＝8.34Hz，1H)，7.60-7.68(m，2H)，7.68-7.76(m，2H)，8.54(d，J＝9.35Hz，1H)。
Compound 94:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-methyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, in the presence of sodium hydroxide solution, make intermediate 80 and intermediate 78 reactions.Acquisition is the compound 94 of fine hair shape light yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.35-1.39(m，2H)，1.50-1.54(m，2H)，2.55(s，3H)，7.18(dt，J＝8.8，2.5Hz，2H)，7.29(dt，J＝8.8，2.5Hz，2H)，7.83(s，1H)，8.60(s，1H)。
Compound 95:6-chloro-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.63g is 2.5mmol) with intermediate 78 (0.70g, 3.3mmol) reaction to make intermediate 82.Acquisition is the compound 95 (28mg, 2.5% productive rate) of fine hair shape light yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.33-1.37(m，2H)，1.48-1.52(m，2H)，7.18(ddd，2H)，7.28(ddd，J＝8.8，2.5，2.3Hz，2H)，7.90(d，J＝2.3Hz，1H)，9.20(d，J＝2.0Hz，1H)。
Compound 96:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-phenyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.89g is 3.1mmol) with intermediate 78 (0.84g, 4.0mmol) reaction to make intermediate 83.Acquisition is fine hair shape bright yellow solid compound 96 (95mg, 6.4% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.37-1.41(m，2H)，1.53-1.57(m，2H)，7.20(ddd，J＝8.9，2.7，2.3Hz，2H)，7.28-7.32(m，2H)，7.45-7.50(m，1H)，7.56(t，J＝7.6Hz，2H)，7.77-7.81(m，2H)，8.17(d，J＝2.0Hz，1H)，9.20(d，J＝1.8Hz，1H)。
Compound 97:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-methyl-6-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.259g is 1.13mmol) with intermediate 78 (0.31g, 1.5mmol) reaction to make intermediate 88.Acquisition is the compound 97 (31.6mg, 6.6% productive rate) of fine hair shape light yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.36-1.41(m，2H)，1.55-1.59(m，2H)，2.80(s，3H)，7.15-7.20(m，2H)，7.28(ddd，J＝8.9，2.5，2.2Hz，2H)，7.69(s，1H)，8.99(s，1H)。
Compound 98:2-(1-(4-chloro-phenyl-) cyclopropyl-6-ethyl-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.271g is 1.11mmol) with intermediate 78 (0.31g, 1.5mmol) reaction to make intermediate 89.Acquisition is the compound 98 (66mg, 14% productive rate) of fine hair shape light yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.27(t，J＝7.6Hz，3H)，1.33-1.39(m，2H)，1.48-1.54(m，2H)，2.85(q，J＝7.4Hz，2H)，7.14-7.20(m，2H)，7.25-7.32(m，2H)，7.85(d，J＝1.5Hz，1H)，8.67(s，1H)。
Compound 99:2-(1-(4-chloro-phenyl-) cyclopropyl)-8-ethyl-3-hydroxyl-6-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.377g is 1.55mmol) with intermediate 78 (0.39g, 1.9mmol) reaction to make intermediate 90.Acquisition is the compound 99 (106mg, 16% productive rate) of fine hair shape light yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.33(t，J＝7.5Hz，3H)，1.36-1.41(m，2H)，1.52-1.57(m，2H)，3.28(q，J＝7.4Hz，2H)，7.17-7.22(m，2H)，7.26-7.31(m，2H)，7.64(d，J＝2.0Hz，1H)，9.03(s，1H)。
Compound 100:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-phenyl-6-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.521g is 1.79mmol) with intermediate 78 (0.45g, 2.2mmol) reaction to make intermediate 91.Acquisition is the compound 100 (196mg, 23% productive rate) of fine hair shape yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.28-1.33(m，2H)，1.49-1.55(m，2H)，7.08(d，J＝8.6Hz，2H)，7.25(d，J＝8.6Hz，2H)，7.45(t，J＝7.3Hz，1H)，7.52(t，J＝7.3Hz，2H)，7.69(d，J＝7.1Hz，2H)，7.77(d，J＝1.8Hz，1H)，9.14(s，1H)。
Compound 101:3-hydroxyl-6-methyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.415g is 1.81mmol) with intermediate 92 (0.42g, 2.4mmol) reaction to make intermediate 80.Acquisition is the compound 101 (70mg, 10% productive rate) of fine hair shape yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.33-1.39(m，2H)，1.45-1.52(m，2H)，2.55(s，3H)，7.11-7.20(m，3H)，7.21-7.27(m，2H)，7.83(d，J＝1.3Hz，1H)，8.61(s，1H)。
Compound 102:3-hydroxyl-6-phenyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.504g is 1.73mmol) with intermediate 92 (0.40g, 2.3mmol) reaction to make intermediate 83.Acquisition is fine hair shape bright yellow solid compound 102 (75mg, 9.7% productive rate). 1H?NMR(400MHz，DMSO-d 6)δ1.36-1.42(m，2H)，1.50-1.55(m，2H)，7.13-7.21(m，3H)，7.22-7.28(m，2H)，7.48(t，J＝7.2Hz，1H)，7.57(t，J＝7.7Hz，2H)，7.79(d，J＝7.1Hz，2H)，8.18(d，J＝1.8Hz，1H)，9.20(d，J＝1.8Hz，1H)。
Compound 103:6-bromo-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.438g is 1.49mmol) with intermediate 78 (0.41g, 1.9mmol) reaction to make intermediate 93.Acquisition is the compound 103 (26mg, 3.5% productive rate) of fine hair shape yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.32-1.37(m，2H)，1.48-1.52(m，2H)，7.18(ddd，J＝8.9，2.5，2.2Hz，2H)，7.28(ddd，J＝8.8，2.4，2.2Hz，2H)，7.96(d，J＝2.0Hz，1H)，9.41(d，J＝2.0Hz，1H)。
Compound 104:6-ethyl-3-hydroxyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.417g is 1.71mmol) with intermediate 92 (0.39g, 2.2mmol) reaction to make intermediate 89.Acquisition is the compound 104 (26mg, 3.8% productive rate) of fine hair shape yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.27(t，J＝1.5Hz，3H)，1.32-1.38(m，2H)，1.46-1.51(m，2H)，2.85(q，J＝7.6Hz，2H)，7.11-7.18(m，3H)，7.20-7.26(m，2H)，7.84(d，J＝1.8Hz，1H)，8.67(s，1H)。
Compound 105:3-hydroxyl-2-(1-(4-chloro-phenyl-) cyclopropyl)-6, two (trifluoromethyl) quinoline of 8--4-formic acid
According to for the described program of the preparation of compound 14, (0.431g is 1.52mmol) with intermediate 78 (0.349g, 1.98mmol) reaction to make intermediate 96.Acquisition is the compound 105 (13mg, 1.9% productive rate) of fine hair shape yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.33-1.38(m，2H)，1.47-1.52(m，2H)，7.11-7.17(m，1H)，7.17-7.26(m，4H)，8.00(d，J＝1.8Hz，1H)，9.77(s，1H)。
Compound 106:2-(1-(4-chloro-phenyl-) cyclopropyl-3-hydroxyl-6,8-pair-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.431g is 1.52mmol) with intermediate 92 (0.417g, 1.98mmol) reaction to make intermediate 96.Acquisition is the compound 106 (6.5mg, 0.9% productive rate) of fine hair shape light yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.32-1.36(m，2H)，1.49-1.53(m，2H)，7.19(ddd，J＝8.9，2.7，2.3Hz，2H)，7.28(ddd，J＝9.0，2.5，2.4Hz，2H)，7.94(d，J＝1.8Hz，1H)，9.91(s，1H)。
Compound 107:6-bromo-3-hydroxyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (0.400g is 1.36mmol) with intermediate 92 (0.31g, 1.8mmol) reaction to make intermediate 93.Acquisition is the compound 107 (5.5mg, 0.9% productive rate) of fine hair shape light yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.28-1.33(m，2H)，1.42-1.46(m，2H)，7.09-7.15(m，1H)，7.15-7.24(m，4H)，7.87(d，J＝2.3Hz，1H)，9.63(d，J＝2.3Hz，1H)。
Compound 108:2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4, the 8-dioctyl phthalate
According to for the described program of the preparation of compound 14, make 2, (0.502g is 2.63mmol) with intermediate 78 (0.72g, 3.4mmol) reaction for 3-dioxo indoline-7-formic acid.Acquisition is the compound 108 (8.4mg, 0.8% productive rate) of fine hair shape light yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ1.41-1.47(m，2H)，1.51-1.56(m，2H)，7.23-7.28(m，2H)，7.28-7.34(m，2H)，7.71(dd，J＝8.6，7.3Hz，1H)，8.26(dd，J＝7.2，1.4Hz，1H)，9.23(d，J＝8.1Hz，1H)。
Compound 109:2-[1-(4-chloro-phenyl)-cyclopropyl]-8-cyclopropyl-3-hydroxyl-quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make intermediate 94 (7-cyclopropyl-1H-indoles-2,3-diketone, 100mg, 0.53mmol) and intermediate 55 (acetate 2-[1-(4-chloro-phenyl)-cyclopropyl]-2-oxo-ethyl ester, 130mg, 0.52mmol) reaction.Acquisition is the compound 109 (30mg, 15.2% productive rate) of yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ0.81-0.86(m，2H)，1.07-1.14(m，2H)，1.34-1.39(dd，J＝6.57，4.55Hz，2H)，1.53-1.57(dd，J＝6.57，4.04Hz，2H)，3.22-3.30(m，1H)，7.00(d，J＝7.33Hz，1H)，7.16(d，J＝8.84Hz，2H)，7.27(d，J＝8.84Hz，2H)，7.44(dd，J＝7.33，7.07Hz，1H)，8.37(d，J＝7.07Hz，1H)。
Compound 110:8-cyclopropyl-3-hydroxyl-2-(1-phenyl-cyclopropyl)-quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (100mg is 0.53mmol) with intermediate 8 (acetate 2-oxo-2-(1-phenyl-cyclopropyl)-ethyl ester, 116mg, 0.53mmol) reaction for 7-cyclopropyl-1H-indoles-2,3-diketone to make intermediate 94.Acquisition is the compound 110 (13.0mg, 7.1% productive rate) of yellow solid. 1H?NMR(400MHz，DMSO-d 6)δ0.82-0.87(m，2H)，1.08-1.14(m，2H)，1.36(dd，J＝6.82，4.55Hz，2H)，1.53(dd，J＝6.82，5.05Hz，2H)，3.22-3.30(m，1H)，7.00(d，J＝8.34Hz，1H)，7.12-7.17(m，2H)，7.19-7.26(m，3H)，7.45(dd，J＝8.34，7.07Hz，1H)，8.32-8.39(d，J＝7.07Hz，1H)。
Compound 111:3-hydroxyl-2-(1-phenyl-cyclopropyl methyl)-8-fluoroform yl-quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (35mg is 0.16mmol) with intermediate 98 (1-hydroxyl-3-(1-phenyl-cyclopropyl)-third-2-ketone, 30mg, 0.16mmol) reaction for 7-(trifluoromethyl) indoline-2,3-diketone to make intermediate 6.Acquisition is the compound 111 (5.0mg, 8.0% productive rate) of beige solid. 1H?NMR(400MHz，MeOD)δ0.77(dd，J＝6.06，4.29Hz，2H)，0.97(dd，J＝5.81，4.29Hz，2H)，3.32(s，2H)，6.91-7.04(m，3H)，7.10-7.14(m，2H)，7.51(dd，J＝8.84，7.33Hz，1H)，7.78(d，J＝7.33Hz，1H)，8.94(d，J＝8.84Hz，1H)。
Compound 112:2-(1-phenmethyl-cyclopropyl)-3-hydroxyl-8-fluoroform yl-quinoline-4-formic acid
According to for the described program of the preparation of compound 14, (310mg is 1.44mmol) with intermediate 100 (1-(1-phenmethyl-cyclopropyl)-2-hydroxyl-ethyl ketone, 273mg, 1.44mmol) reaction for 7-(trifluoromethyl) indoline-2,3-diketone to make intermediate 6.Acquisition is the compound 112 (19.0mg, 3.4% productive rate) of yellow solid. 1H?NMR(400MHz，MeOD)δ1.14-1.18(m，2H)，1.48-1.53(m，2H)，2.24(s，2H)，7.21-7.25(m，1H)，7.26-7.33(m，2H)，7.42-7.47(m，2H)，7.76-7.82(m，1H)，8.05(d，J＝7.33Hz，1H)，9.24(d，J＝8.84Hz，1H)。
Compound 113:3-hydroxyl-7,8-dimethyl-2-(1-p-methylphenyl-cyclopropyl)-quinoline-4-formic acid
According to for the described program of the preparation of compound 14, make intermediate 4 (6,7-dimethyl-1H-indoles-2, the 3-diketone, 263mg is 1.5mmol) with intermediate 77 (2-hydroxyl-1-(1-p-methylphenyl-cyclopropyl)-ethyl ketone, 357mg, 1.88mmol) reaction.Acquisition is the compound 113 (165mg, 31.7% productive rate) of yellow solid. 1H?NMR(400MHz，MeOD)δ1.14-1.18(m，2H)，1.48-1.53(m，2H)，2.24(s，2H)，7.21-7.25(m，1H)，7.26-7.33(m，2H)，7.42-7.47(m，2H)，7.76-7.82(m，1H)，8.05(d，J＝7.33Hz，1H)，9.24(d，J＝8.84Hz，1H)。
Other compound that can serve as the inhibitor of selecting plain (for example palatelet-selectin) can synthesize according to following program.
Compound 114:3-hydroxyl-2-(2-phenyl third-2-yl)-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid
In the 100mL round-bottomed flask that is equipped with condenser, add intermediate 3 (promptly 6,7,8,9-tetrahydrochysene-1H-benzo [g] indoles-2,3-diketone) (1.76g, 7.0mmol, 1.0 equivalents) and 40mL ethanol.In this solution, add 10.0N aqueous sodium hydroxide solution (6.3mL, 63.0mmol, 9.0 equivalents) and in oil bath, mixture heating up is arrived backflow.Under refluxing, continue to stir 30 minutes, dropwise added intermediate 2 (being acetate 3-methyl-2-oxo-3-butyloxy phenyl) (2.0g, 9.09mmol, 1.3 equivalents) solution in 10mL ethanol this moment through 20 minutes.With gained mixture restir 12 hours under refluxing.Behind the cool to room temperature, immediately with excessive glacial acetic acid acidifying mixture and pour in the 200mL water.With three parts of 100mL ethyl acetate extraction suspension, and the organic layer that merges with the washing of three parts of 200mL water and 250mL saturated sodium bicarbonate solution.Via the dried over mgso organic layer, filter and remove in a vacuum solvent to generate dark yellow oily thing.Come this oily matter of purifying and freeze-drying to be the required product (0.0315g, 1.3%) of yellow lyophilized powder with generation by reversed-phase HPLC (basic methods 3). 1H?NMR(400MHz，DMSO-d 6)δppm?1.79(s，6H)1.81-1.98(m，4H)2.74-2.94(m，2H)3.22-3.46(m，2H)7.08-7.16(m，3H)7.18-7.26(m，2H)7.29(d，J＝8.84Hz，1H)8.36(d，J＝9.09Hz，1H)。
Compound 115:3-hydroxyl-7,8-dimethyl-2-(2-phenyl third-2-yl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with intermediate 4 (promptly 6,7-dimethyl indole quinoline-2, the 3-diketone) (1.0g, 5.71mmol, 1.0 equivalents) and 10.0N aqueous sodium hydroxide solution (5.1mL, 51.4mmol, 9.0 equivalent) handle intermediate 2 (being acetate 3-methyl-2-oxo-3-butyloxy phenyl) (1.65g, 7.4mmol, 1.3 equivalents).Isolate the required product (0.190g, 10%) that is yellow lyophilized powder. 1H?NMR(400MHz，DMSO-d 6)δppm1.81(s，6H)2.44(s，3H)2.75(s，3H)7.09-7.16(m，3H)7.19-7.27(m，2H)7.41(d，J＝8.84Hz，1H)8.36(d，J＝8.84Hz，1H)。
Compound 116:3-hydroxyl-8-sec.-propyl-2-(2-phenyl third-2-yl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with intermediate 5 (is 7-isopropyl indole quinoline-2, the 3-diketone) (1.0g, 5.29mmol, 1.0 equivalent) and 10.0N aqueous sodium hydroxide solution (4.8mL, 47.6mmol, 9.0 equivalents) handle intermediate 2 (being acetate 3-methyl-2-oxo-3-butyloxy phenyl) (0.80g, 3.6mmol, 0.7 equivalent).Isolate the required product (0.068g, 4%) that is yellow lyophilized powder. 1H?NMR(400MHz，DMSO-d 6)δppm?1.39(d，J＝7.07Hz，6H)1.81(s，6H)3.56-4.87(h，J＝7.07Hz，1H)7.04-7.18(m，3H)7.19-7.28(m，2H)7.47(d，J＝8.341H)7.53(t，J＝8.341H)8.41(d，J＝8.34Hz，1H)。
Compound 117:3-hydroxyl-2-(2-phenyl third-2-yl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with intermediate 6 (is 7-(trifluoromethyl) indoline-2, the 3-diketone) (1.5g, 6.98mmol, 1.0 equivalent) and 10.0N aqueous sodium hydroxide solution (6.2mL, 62.8mmol, 9.0 equivalents) handle intermediate 2 (being acetate 3-methyl-2-oxo-3-butyloxy phenyl) (2.01g, 9.07mmol, 1.3 equivalents).Isolate the required product (0.486g, 19%) that is yellow lyophilized powder. 1H?NMR(400MHz，DMSO-d 6)δppm?1.78(s，6H)6.96-7.19(m，3H)7.19-7.30(m，2H)7.69(t，J＝8.081H)7.95(d，J＝6.82Hz，1H)8.98(d，J＝8.08Hz，1H)。
Compound 118: 2-(2-(4-chloro-phenyl-) third-2-yl)-3-hydroxyl-8-isopropyl quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with acetate 3-(4-chloro-phenyl-)-3-methyl-2-oxo butyl ester (intermediate 56,99mg, 0.39mmol) to handle intermediate 5 (be 7-isopropyl indole quinoline-2, the 3-diketone) (74mg, 0.39mmol) be the required product (9.8mg, 6.6%) of yellow solid with generation. 1H NMR (400MHz, MeOH-D 4) δ ppm 1.63 (d, J=7.1Hz, 6H), 2.04-2.10 (s, 6H), 4.61 (septet, J=7.1Hz, 1H), 7.37 (d, J=8.6Hz, 2H), 7.43 (d, J=8.6Hz, 2H), 7.66-7.76 (m, 2H), 8.82 (dd, J=8.6,1.5Hz, 1H).
Compound 119:2-(2-(4-chloro-phenyl-) third-2-yl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with acetate 3-(4-chloro-phenyl-)-3-methyl-2-oxo butyl ester (intermediate 56,99mg, 0.39mmol) to handle intermediate 6 (be 7-(trifluoromethyl) indoline-2, the 3-diketone) (85mg, 0.39mmol) be the required product (15.0mg, 9.4%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm?2.01-2.10(s，6H)，7.36(d，J＝9.0Hz，2H)，7.43(d，J＝9.0Hz，2H)，7.86(dd，J＝8.6，7.7Hz，1H)，8.15(d，J＝7.7Hz，1H)，9.25(d，J＝8.6Hz，1H)。
Compound 120:2-(2-(4-chloro-phenyl-) third-2-yl)-3-hydroxyl-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid
According to for the described program of the preparation of compound 114, (intermediate 56,99mg 0.39mmol) handle intermediate 3 (80mg with acetate 3-(4-chloro-phenyl-)-3-methyl-2-oxo butyl ester, 0.39mmol) be the required product (6.2mg, 4.0%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm?2.03-2.07(s，6H)，2.08-2.24(m，4H)，3.09-3.17(m，2H)，3.57-3.62(m，2H)，7.36(d，J＝9.0Hz，2H)，7.42(d，J＝9.0Hz，2H)，7.49(d，J＝9.0Hz，1H)，8.77(d，J＝9.0Hz，1H)。
Compound 121:2-(2-(4-chloro-phenyl-) third-2-yl)-3-hydroxyl-7,8-dimethyl quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with acetate 3-(4-chloro-phenyl-)-3-methyl-2-oxo butyl ester (intermediate 56,99mg, 0.39mmol) handle intermediate 4 (promptly 6,7-dimethyl indole quinoline-2, the 3-diketone) (70mg 0.39mmol) is the required product (11.9mg, 8.3%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm?2.04-2.09(s，6H)，2.66-2.72(s，3H)，2.98-3.05(s，3H)，7.36(d，J＝8.5Hz，2H)，7.42(d，J＝8.5Hz，2H)，7.57(d，J＝8.5Hz，1H)，8.78(d，J＝8.5Hz，1H)。
Compound 122:2-(2-(4-chloro-phenyl-) third-2-yl)-8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyl quinoline Quinoline-4-formic acid
According to for the described program of the preparation of compound 114, (0.39mmol) handling intermediate 16 (is 7-(1 for intermediate 56,99mg with acetate 3-(4-chloro-phenyl-)-3-methyl-2-oxo butyl ester, 1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl) indoline-2, the 3-diketone) (130mg 0.39mmol) is the required product (14.0mg, 7.1%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm?2.04-2.10(m，3H，)2.24-2.29(m，3H)，7.36(d，J＝8.3Hz，2H)，7.48(d，J＝8.3Hz，2H)，7.96(dd，J＝9.3，8.3Hz，1H)，8.16(d，J＝8.3Hz，1H)，9.19(d，J＝9.3Hz，1H)。
Compound 123:3-hydroxyl-2-(1-phenylethyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with intermediate 6 (is 7-(trifluoromethyl) indoline-2, the 3-diketone) (0.740g, 3.44mmol, 1.0 equivalents) and 10.0N sodium hydroxide (2.8mL, 27.5mmol, 8.0 equivalent) handle intermediate 40 (being acetate 2-oxo-3-butyloxy phenyl) (0.922g, 4.47mmol, 1.3 equivalents) and be the required product (0.450g, 36%) of orange lyophilized powder with generation. 1H?NMR(400MHz，DMSO-d 6)δppm1.68(d，J＝7.07Hz，3H)4.87(q，J＝7.07Hz，1H)6.90-7.41(m，5H)7.69(t，J＝6.82Hz，1H)7.97(d，J＝6.82Hz，1H)8.84(d，J＝8.34Hz，1H)。
Compound 124:2-(1-(4-chloro-phenyl-) ethyl)-3-hydroxyl-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid
According to by Daniel Craig's people's (organic chemistry magazines (J.Org.Chem.) such as (Cragoe), 1953,18,561) described program, under 100 ℃ through 0.5 hour period to intermediate 3 (0.16g, 0.8mmol) in the mixture in the 0.5mL EtOH and the 1mL 6M KOH aqueous solution with aliquot add the warm acetate 3-in 0.5mL EtOH (4-chloro-phenyl-)-2-oxo butyl ester (intermediate 53,0.21g, 0.9mmol).After finishing interpolation, the reaction mixture certain hour that refluxes is again finished up to the LC/MS Indicator Reaction.After removing solvent, the gained yellow jelly is dissolved among the 1mLDMSO.Under alkaline condition (triethylamine), gained DMSO solution is carried out HPLC, obtain being the required product of triethyl ammonium salt.Make described salt be dissolved in the 1mL acetonitrile subsequently and under 0 ℃, be acidified to the pH value and be about 1 with concentrated hydrochloric acid.Add water (20mL) and 0 ℃ of following vigorous stirring gained suspension 1 hour.Via filter collecting yellow solid, wash with water and dry to generate required product (17mg, 5.6%) under vacuum. 1H?NMR(400MHz，MeOH-D 4)δppm?1.69(d，J＝7.0Hz，3H)，1.80-1.97(m，4H)，2.79-2.88(m，2H)，3.25-3.35(m，2H)，4.81(q，J＝7.0Hz，1H)，7.12(d，J＝9.6Hz，1H)，7.18(d，J＝8.5Hz，2H)，7.34(d，J＝8.5Hz，2H)，8.80(d，J＝9.6Hz，1H)。
Compound 125:3-hydroxyl-2-(1-phenylethyl)-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid
In the 25mL round-bottomed flask that is equipped with condenser, add intermediate 3 (promptly 6,7,8,9-tetrahydrochysene-1H-benzo [g] indoles-2,3-diketone) (0.176g, 0.7mmol, 1.0 equivalents) and 4mL ethanol.In this solution, add 10.0N aqueous sodium hydroxide solution (0.63mL, 6.3mmol, 9.0 equivalents) and in oil bath, mixture heating up is arrived backflow.Added the solution of intermediate 40 (being acetate 2-oxo-3-butyloxy phenyl) (0.187g, 0.91mmol, 1.3 equivalents) in 1.0mL ethanol through 60 minutes in this solution of clockwise.With gained mixture restir 3 hours under refluxing.Behind the cool to room temperature, and under reduced pressure remove ethanol immediately.Mixture is acidified to pH 1 and pours in the water with 1M HCl.The required product (0.102g, 42%) that comes thick solid that purifying obtains and freeze-drying to be yellow lyophilized powder with generation by reversed-phase HPLC (water/acetonitrile/0.1% triethylamine). 1H?NMR(400MHz，DMSO-d 6)δppm?1.68(d，J＝6.8Hz，3H)1.75-1.96(m，4H)2.84(t，J＝6.7Hz，2H)3.30(t，J＝6.8Hz，1H)4.71-4.93(m，1H)7.14(t，J＝8.0Hz，1H)7.20-7.29(m，3H)7.33(d，J＝7.6Hz，2H)8.14-8.38(m，1H)。
Compound 126:3-hydroxyl-2-(1-phenyl propyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxyl-3-phenyl penta-2-ketone (intermediate 57,180mg, 1.00mmol) to handle intermediate 6 (be 7-(trifluoromethyl) indoline-2, the 3-diketone) (200mg, 0.93mmol) be the required product (100.7mg, 28.7%) of faint yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm?1.11(t，J＝7.5Hz，3H)，2.30-2.42(m，1H)，2.64-2.77(m，1H)，4.85(t，J＝8.2Hz，1H)，7.31-7.38(m，1H)，7.40-7.48(m，2H)，7.63(d，2H)，7.85(dd，J＝8.3，7.6Hz，1H)，8.14(d，J＝7.6Hz，1H)，9.29(d，J＝8.3Hz，1H)。
Compound 127:3-hydroxyl-8-sec.-propyl-2-(1-phenyl propyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxyl-3-phenyl penta-2-ketone (intermediate 57,130mg, 0.73mmol) to handle intermediate 5 (be 7-isopropyl indole quinoline-2, the 3-diketone) (124.7mg, 0.66mmol) be the required product (30.8mg, 13.4%) of yellow solid with generation. 1H NMR (400MHz, MeOH-D 4) δ ppm1.14 (t, J=7.5Hz, 3H), 1.63 (d, J=6.7Hz, 6H), and 2.28-2.45 (m, 1H), 2.64-2.81 (m, 1H), 4.54-4.70 (septet, J=6.7Hz, 1H), 4.86 (t, J=7.5Hz, 1H), and 7.32-7.38 (m, 1H), 7.46 (dd, J=6.7,6.7Hz, 2H), 7.61 (d, J=7.6Hz, 2H), 7.64-7.77 (m, 2H), 8.86 (d, J=8.4Hz, 1H).
Compound 128: 3-hydroxyl-7,8-dimethyl-2-(1-phenyl propyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxyl-3-phenyl penta-2-ketone (intermediate 57,130mg, 0.74mmol) handle intermediate 4 (promptly 6,7-dimethyl indole quinoline-2, the 3-diketone) (130.0mg is 0.66mmol) with the generation required product of solid (39.0mg, 15.7%) that is white in color. 1H?NMR(400MHz，MeOH-D 4)δppm1.14(t，J＝7.7Hz，3H)，2.31-2.47(m，1H)，2.63-2.78(m，1H)，2.68(s，3H)，3.00(s，3H)，4.83(t，J＝7.7Hz，1H)，7.31-7.33(m，1H)，7.42-7.44(m，2H)，7.55(d，J＝8.6Hz，1H)，7.62(d，J＝8.2Hz，2H)，8.75(d，J＝9.0Hz，1H)。
Compound 129:3-hydroxyl-2-(2-methyl isophthalic acid-phenyl propyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxy-4-methyl-3-phenyl penta-2-ketone (intermediate 59,147mg, 0.76mmol) to handle intermediate 6 (be 7-(trifluoromethyl) indoline-2, the 3-diketone) (150mg, 0.70mmol) with the generation required product of solid (43.7mg, 16.0%) that is white in color. 1H?NMR(400MHz，MeOH-D 4)δppm?1.04(d，J＝6.5Hz，3H)，1.12(d，J＝6.5Hz，3H)，3.11-3.25(m，1H)，4.57(d，J＝10.6Hz，1H)，7.28-7.34(m，1H)，7.41(dd，J＝7.2，7.1Hz，2H)，7.69(d，J＝7.7Hz，1H)，7.73(d，J＝8.3Hz，2H)，7.99(d，J＝7.1Hz，1H)，9.75(d，J＝8.9Hz，1H)。
Compound 130:3-hydroxyl-8-sec.-propyl-2-(2-methyl isophthalic acid-phenyl propyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxy-4-methyl-3-phenyl penta-2-ketone (intermediate 59,130mg, 0.68mmol) to handle intermediate 5 (be 7-isopropyl indole quinoline-2, the 3-diketone) (119mg, 0.63mmol) be the required product (8.1mg, 3.5%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm1.08(d，J＝6.5Hz，3H)，1.15(d，J＝6.5Hz，3H)，1.64(d，J＝7.1Hz，3H)，1.66(d，J＝7.1Hz，3H)，3.15-3.28(m，1H)，4.60(d，J＝10.5Hz，1H)，4.60-4.70(m，1H)，7.31-7.38(m，1H)，7.40-7.47(m，2H)，7.64-7.74(m，4H)，8.80-8.88(m，1H)。
Compound 131:3-hydroxyl-7,8-dimethyl-2-(2-methyl isophthalic acid-phenyl propyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxy-4-methyl-3-phenyl penta-2-ketone (intermediate 59,126mg, 0.66mmol) handle intermediate 4 (promptly 6,7-dimethyl indole quinoline-2, the 3-diketone) (105mg 0.60mmol) is the required product (12.5mg, 6.0%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm?1.08(d，J＝6.7Hz，3H)，1.15(d，J＝6.7Hz，3H)，2.69(s，3H)，3.04(s，3H)，3.15-3.28(m，1H)，4.57(d，J＝10.8Hz，1H)，7.30-7.36(m，1H)，7.40-7.46(m，2H)，7.54(d，J＝8.9Hz，1H)，7.68-7.74(m，2H)，8.76(d，J＝8.9Hz，1H)。
Compound 132:3-hydroxyl-2-(1-phenyl third-2-yl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxy-3-methyl-4-phenyl fourth-2-ketone (intermediate 60,136mg, 0.76mmol) to handle intermediate 6 (be 7-(trifluoromethyl) indoline-2, the 3-diketone) (150mg, 0.70mmol) be the required product (51.6mg, 19.6%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm?1.50(s，3H)，3.07(dd，J＝13.4，7.4Hz，1H)，3.57(dd，J＝13.4，7.4Hz，1H)，4.10-4.23(m，1H)，7.25-7.42(m，5H)，7.80(dd，J＝8.5，8.0Hz，1H)，8.09(d，J＝7.4Hz，1H)，9.35(d，J＝8.5Hz，1H)。
Compound 133:3-hydroxyl-8-sec.-propyl-2-(1-phenyl third-2-yl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxy-3-methyl-4-phenyl fourth-2-ketone (intermediate 60,136mg, 0.76mmol) to handle intermediate 5 (be 7-isopropyl indole quinoline-2, the 3-diketone) (130mg, 0.70mmol) be the required product (14.0mg, 5.7%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm1.54-1.62(m，9H)，3.11(dd，J＝13.4，7.6Hz，1H)，3.54-3.59(dd，J＝13.4，6.9Hz，1H)，4.12-4.22(m，1H)，4.52-4.62(m，1H)，7.27-7.34(m，1H)，7.34-7.43(m，4H)，7.62-7.72(m，2H)，8.82(dd，dd，J＝8.3，1.8Hz，1H)。
Compound 134:3-hydroxyl-7,8-dimethyl-2-(1-phenyl third-2-yl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxy-3-methyl-4-phenyl fourth-2-ketone (intermediate 60,136mg, 0.76mmol) handle intermediate 4 (promptly 6,7-dimethyl indole quinoline-2, the 3-diketone) (126mg 0.70mmol) is the required product (13.0mg, 5.5%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm?1.55(d，J＝6.8Hz，3H)，2.67(s，3H)，2.96(s，3H)，3.09(dd，J＝12.8，7.2Hz，1H)，3.59(dd，J＝12.8，7.2Hz，1H)，4.06-4.20(m，1H)，7.27-7.35(m，1H)，7.35-7.43(m，4H)，7.55(d，J＝8.8Hz，1H)，8.73(d，J＝8.8Hz，1H)。
Compound 135:3-hydroxyl-2-(2-phenyl propyl)-8-(trifluoromethyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxy-4-phenyl penta-2-ketone (intermediate 61,136mg, 0.76mmol) to handle intermediate 6 (be 7-(trifluoromethyl) indoline-2, the 3-diketone) (150mg, 0.70mmol) with the generation required product of solid (46.1mg, 17.6%) that is white in color. 1H?NMR(400MHz，MeOH-D 4)δppm1.56(d，J＝7.1Hz，3H)，3.47(dd，J＝14.7，8.4Hz，1H)，3.64(dd，J＝14.7，6.7Hz，1H)，3.85-3.96(m，1H)，7.28-7.35(m，1H)，7.43(dd，J＝7.6，7.6Hz，2H)，7.50(d，J＝7.6Hz，2H)，7.82(dd，J＝8.4，7.6Hz，1H)，8.10(d，J＝7.6Hz，1H)，9.26(d，J＝8.4Hz，1H)。
Compound 136:3-hydroxyl-8-sec.-propyl-2-(2-phenyl propyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxy-4-phenyl penta-2-ketone (intermediate 61,136mg, 0.76mmol) to handle intermediate 5 (be 7-isopropyl indole quinoline-2, the 3-diketone) (130mg, 0.70mmol) be the required product (22.4mg, 9.2%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm?1.32(d，J＝7.0Hz，3H)，1.36(d，J＝6.5Hz，3H)，1.42(d，J＝7.0Hz，3H)，3.37-3.40(m，1H)，3.41-3.50(m，1H)，3.63-3.72(m，1H)，4.24-4.36(m，1H)，7.13-7.19(m，1H)，7.22-7.35(m，4H)，7.42-7.55(m，2H)，8.70(d，J＝8.1Hz，1H)。
Compound 137:3-hydroxyl-7,8-dimethyl-2-(2-phenyl propyl) quinoline-4-formic acid
According to for the described program of the preparation of compound 114, with 1-hydroxy-4-phenyl penta-2-ketone (intermediate 61,136mg, 0.76mmol) handle intermediate 4 (promptly 6,7-dimethyl indole quinoline-2, the 3-diketone) (126mg 0.70mmol) is the required product (27.7mg, 11.8%) of yellow solid with generation. 1H?NMR(400MHz，MeOH-D 4)δppm1.61(d，J＝7.2Hz，3H)，2.65(s，3H)，2.82(s，3H)，3.57-3.66(m，2H)，3.76-3.89(m，1H)，7.29-7.37(m，1H)，7.40-7.50(m，4H)，7.59(d，J＝8.6Hz，1H)，8.80-8.95(m，1H)。
Compound 138:2-(4-chlorophenylmethyl)-3-[(morpholine-4-base carbonyl) oxygen base]-7,8,9,10-tetrahydro benzo [h] quinoline-4- Formic acid
Under 25 ℃, with 2-(4-chlorophenylmethyl)-3-hydroxyl-7,8,9, (0.124g is 0.338mmol) (as medical chemistry magazine (J.Med.Chem.) 2007 for 10-tetrahydro benzo [h] quinoline-4-formic acid, 50, described in 40 and prepare), 4-morpholine carbonyl chloride (42 μ L, 0.37mmol), triethylamine (52 μ L, 0.37mmol) and the mixture of 1.0mL THF/1.0mL pyridine stirred 16 hours.Concentrated reaction mixture produces the oiliness resistates.Under alkaline condition, resistates is carried out the HPLC purifying and obtain white solid, be about 1 with 1N HCl acidified aqueous solution to the pH value down at 0 ℃.By filtering the collecting precipitation thing, wash with water and dry with the generation solid product (12.5mg, 7.7%) that is white in color under vacuum. 1H?NMR(400MHz，MeOD-D 6)：δ1.85-1.98(m，4H)，2.87-2.97(m，2H)，3.23-3.30(m，2H)，3.48-3.67(m，4H)，3.69-3.79(m，4H)，4.21-4.29(m，2H)，7.18-7.28(m，4H)，7.71-7.80(m，2H)。HRMS (ESI+) C 26H 25ClN 20 5(MH +) calculated value 481.15248, experimental value 481.1521.
Bioassay
Bai Keer (Biacore) palatelet-selectin/PSGL-1 suppresses to measure
Under 25 ℃, (visit Kerr Corp (Biacore Inc.) at Bai Keer 3000 instruments, New Jersey Pi Sikata (Piscataway, NJ)) go up with the flow velocity execution list surface plasma resonance of 30 mul/min and measure, and each is measured by balance, 60 μ L samples injections (kinject) in 60 seconds and dissociated in 300 seconds and form.
Via amination reaction (sulfonic group-NHS-LC-vitamin H (Sulfo-NHS-LC-Biotin), Pierre scholar (Peirce)) to the monomer clipped form " 19ek " that contains all essential palatelet-selectins and cross in conjunction with the purifying of the human PSGL-1 of determiner ( Referring toGe Ci people such as (Goetz), cytobiology magazine (J Cell Biol), 1997,137:509-519; With the people such as (Sako) of three sections, cell (Cell), 1995, unique C-terminal lysine residue 83:323-331) carry out biotin labeling ( Referring toSu Mosi people such as (Somers), cell (Cell), 2000,103:467-479), and use HBS-EP damping fluid (visiing Kerr Corp (Biacore Inc.)) and target 600-700RU to be fixed on the Bai Keer SA sensor chip (visiing Kerr Corp (Biacore Inc.)).Make the chip that was coated with reach reequilibrate with HBS-P damping fluid (visiing Kerr Corp (Biacore Inc.)), be added with 1mM CaCl in the described damping fluid 2With 1mM MgCl 2(both avenges company (Fisher) at one's own expense) is to guarantee there is competent calcium the Ca-dependent interaction between acceptor and part.
Test compounds was cultivated 1 hour in 1.1 * Bai Keer mensuration damping fluid.Via 0.2 μ m strainer, use centrifugal each solution of 96 orifice plate forms (Millipore Corp. (Millipore)).Prepare trisodium glycyrrhizinate salt (TCI) in the same manner as described above, as the positive control parallel with test compounds.Shown glycyrrhizin (certified palatelet-selectin antagonist) ( Referring toJ.T. crust (Patton, J.T.), Glycotech Corp. (GlycoTech Corporation), written communications, in May, 2000) in this mensuration with the IC of 1mM 50Suppressing palatelet-selectin/PSGL-1 interacts.
With the solubility of human palatelet-selectin reorganization clipped form P-LE (being included in the agglutinin territory and epidermal growth factor-like (EGF) territory of expressing in the Chinese hamster ovary celI) ( Referring toSu Mosi people such as (Somers), cell (Cell), 2000,103:467-479) add in each filtered test compounds solution.The ultimate density of reagent is 500nM P.LE, 250 or 500 μ M test compounds (TV structure and decide) or 1mM glycyrrhizin, 10%DMSO and 1 * Bai Keer damping fluid (100mM HEPES, 150mM NaCl, 1mM CaCl 2With 1mM MgCl 2(all reagent all come to avenge at one's own expense company (Fisher)), the pH value is 7.4.Carry out titration further to determine activity under 250 μ M, having active compound.Provide specimen to 96 orifice plates of visiing the kerr instrument device.
The Bai Keer raw data file is outputed in the Excel spreadsheet with the text form, in described software, calculate the mean value of damping fluid blank (experimentizing equally), and from all other samples, deduct described mean value from average untamed P.LE sample neutralization with sample to respectively visiing kerr instrument device chute (Fc).Subsequently, will from its corresponding activity (coating) signal, deduct from the reference signal of Fcl (uncoated) about each injection, this process be called as dual reference ( Referring toMi Zika (Myszka), molecular recognition magazine (J Mol.Recognit.), 1999,12 (5): 279-284).Inhibition signal by will deducting reference value is divided by the not inhibition signal that deducts reference value, deducts this value and income value be multiply by 100 by 1 and come the inhibition per-cent of calculations incorporated.Calculate replicate(determination) the inhibition percent value mean value and be expressed as mean value ± standard deviation.Between the experiment of the inhibition per-cent that in Bai Keer measures, is calculated standard deviation be ± 5.
The measurement result that comprises representative compounds of the present invention in the following table 1.
Table 1
Figure G2008800104747D00881
Figure G2008800104747D00891
Figure G2008800104747D00901
Figure G2008800104747D00911
Figure G2008800104747D00921
Figure G2008800104747D00931
Figure G2008800104747D00941
Figure G2008800104747D00951
Figure G2008800104747D00961
Figure G2008800104747D00971
Figure G2008800104747D00991
Figure G2008800104747D01001
Figure G2008800104747D01011
Figure G2008800104747D01021
Figure G2008800104747D01041
Figure G2008800104747D01051
It will be understood by one of ordinary skill in the art that under the situation that does not break away from spirit of the present invention and can make many variations and modification the above embodiment of the present invention.Wish all described variations all within the scope of the invention.

Claims (43)

1. formula I compound:
Figure A2008800104740002C1
Or its pharmaceutically acceptable salt, hydrate or ester, wherein:
R 1For-OR 9,-C (O) R 10,-C (O) OR 9,-C (O) NR 10R 11,-C (S) R 10,-C (S) OR 9,-C (S) NR 10R 11,-C (NR 10) R 10,-C (NR 10) NR 10R 11,-NR 10R 11,-NR 11C (O) R 10,-NR 11C (O) NR 10R 11,-NR 11C (NR 10) NR 10R 11,-NR 11S (O) mR 10 or-NR 11S (O) mNR 10R 11
R 2For-C (O) OR 9,-C (O) NR 10R 11Or carboxylic acid bioisostere;
R 3And R 3' be independently H ,-CN ,-NO 2, halogen ,-OR 9,-NR 10R 11,-S (O) mR 10,-S (O) mOR 9,-S (O) mNR 10R 11,-C (O) R 10,-C (O) OR 9,-C (O) NR 10R 11,-C (S) R 10,-C (S) OR 9,-C (S) NR 10R 11,-C (NR 10) NR 10R 11, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces; Or
R 3And R 3' form C together with the carbon atom that is connected separately 4-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 4-14 unit ring or 5-14 unit heteroaryl, wherein said C 4-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 4-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 4And R 5Be H, C independently 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces; Or
R 4And R 5Form C together with its corresponding shared carbon atom 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 6And R 7When occurring, be H, C independently at every turn 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces; Or
R 6And R 7Form C together with its corresponding shared carbon atom 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
Condition is R 4And R 5With R 6And R 7In at least one form C together with its corresponding shared carbon atom 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 8Be C 6-14Aryl or 5-14 unit heteroaryl, wherein said C 6-14Aryl and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 9When occurring at every turn independently for H ,-C (O) R 10,-C (O) NR 10R 11,-C (S) R 10,-C (S) NR 10R 11,-C (NR 10) R 10,-C (NR 10) NR 10R 11,-S (O) mR 10, i-S (O) mNR 10R 11, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 10And R 11When occurring at every turn independently for H ,-OH ,-SH ,-S (O) 2OH ,-C (O) OH ,-C (O) NH 2,-C (S) NH 2,-OC 1-10Alkyl ,-C (O)-C 1-10Alkyl ,-C (O)-OC 1-10Alkyl ,-OC 6-14Aryl ,-C (O)-C 6-14Aryl ,-C (O)-OC 6-14Aryl ,-C (S) N (C 1-10Alkyl) 2,-C (S) NH-C 1-10Alkyl ,-C (O) NH-C 1-10Alkyl ,-C (O) N (C 1-10Alkyl) 2,-C (O) NH-C 6-14Aryl ,-S (O) m-C 1-10Alkyl, t-S (O) m-OC 1-10Alkyl, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces;
R 12When occurring at every turn independently for halogen ,-CN ,-NO 2, oxo ,-O-Z-R 13,-NR 13-Z-R 14,-N (O) R 13-Z-R 14,-S (O) mR 13,-S (O) mO-Z-R 13,-S (O) mNR 13-Z-R 14,-C (O) R 13,-C (O) O-Z-R 13,-C (O) NR 13-Z-R 14, n-C (S) NR 13-Z-R 14,-Si (C 1-10Alkyl) 3, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 15Group replaces;
R 13And R 14When occurring at every turn independently for H ,-OH ,-SH ,-S (O) 2OH ,-C (O) OH ,-C (O) NH 2,-C (S) NH 2,-OC 1-10Alkyl ,-C (O)-C 1-10Alkyl ,-C (O)-OC 1-10Alkyl ,-C (S) N (C 1-10Alkyl) 2,-C (S) NH-C 1-10Alkyl ,-C (O) NH-C 1-10Alkyl ,-C (O) N (C 1-10Alkyl) 2,-S (O) m-C 1-10Alkyl ,-S (O) m-OC 1-10Alkyl, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 2-10Thiazolinyl, described C 2-10Alkynyl, described C 3-14Cycloalkyl, described C 6-14Aryl, the assorted alkyl of described 3-14 unit ring and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 15Group replaces;
R 15When occurring at every turn independently for halogen ,-CN ,-NO 2, oxo ,-OH, f)-NH 2,-NH (C 1-10Alkyl) ,-N (C 1-10Alkyl) 2,-S (O) mH ,-S (O) m-C 1-10Alkyl ,-S (O) 2OH ,-S (O) m-OC 1-10Alkyl ,-CHO ,-C (O)-C 1-10Alkyl ,-C (O) OH ,-C (O)-OC 1-10Alkyl ,-C (O) NH 2,-C (O) NH-C 1-10Alkyl ,-C (O) N (C 1-10Alkyl) 2,-C (S) NH 2,-C (S) NH-C 1-10Alkyl ,-C (S) N (C 1-10Alkyl) 2,-S (O) mNH 2,-S (O) mNH (C 1-10Alkyl) ,-S (O) mN (C 1-10Alkyl) 2,-Si (C 1-10Alkyl) 3, C 1-10Alkyl, C 2-10Thiazolinyl, C 2-10Alkynyl, C 1-10Alkoxyl group, C 1-10Alkylhalide group, C 3-14Cycloalkyl, C 6-14Aryl, the assorted alkyl of 3-14 unit ring or 5-14 unit heteroaryl;
Z is divalence C at every turn independently when occurring 1-10Alkyl, divalence C 2-10Thiazolinyl, divalence C 2-10Alkynyl, divalence C 1-10Alkylhalide group or covalent linkage;
M is 0,1 or 2 when occurring at every turn independently; And
N is 0,1 or 2.
2. compound according to claim 1 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 1For-OR 9,-OC (O) R 10Or-NR 10R 11R wherein 9, R 10And R 11Such as claim 1 definition.
3. compound according to claim 2 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 1For-OH.
4. compound according to claim 1 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 2For-C (O) OH.
5. compound according to claim 1 or its pharmaceutically acceptable salt, hydrate or ester, wherein said compound has formula Ia, formula Ib, formula Ic, formula Id, formula Ie or formula If:
Figure A2008800104740005C1
Figure A2008800104740006C1
R wherein 1, R 2, R 3, R 3', R 4, R 5, R 6, R 7, R 8With n such as claim 1 definition.
6. compound according to claim 1 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 3And R 3' be independently H, halogen ,-OR 9,-C (O) OR 9, C 1-10Alkyl, C 3-14Cycloalkyl, C 6-14Aryl or 5-14 unit heteroaryl, wherein said C 1-10Alkyl, described C 3-14Cycloalkyl, described C 6-14Aryl and described 5-14 unit heteroaryl are respectively randomly through 1-4-Z-R 12Group replaces; And R 9, R 12With Z such as claim 1 definition.
7. compound according to claim 1 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 3And R 3' be independently H, halogen ,-CF 3, C 1-10Alkyl, C 3-14Cycloalkyl ,-CO 2H ,-OC 1-10Alkyl ,-OCF 3,-C (CF 3) 2OH, phenyl or 5-14 unit heteroaryl.
8. compound according to claim 1 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 3And R 3' in one to be H and another person be-CF 3
9. compound according to claim 1 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 3And R 3' in one be-C (CF 3) 2OH.
10. compound according to claim 1 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 3And R 3' form C together with the carbon atom that is connected separately 4-14Cycloalkyl or the assorted alkyl of 4-14 unit ring, wherein said C 4-14Cycloalkyl and the assorted alkyl of described 4-14 unit ring are respectively randomly through 1-4-Z-R 12Group replaces, and Z and R 12Such as claim 1 definition.
11. compound according to claim 10 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 3And R 3' form C together with the carbon atom that is connected separately 6Cycloalkyl.
12. compound according to claim 11 or its pharmaceutically acceptable salt, hydrate or ester, wherein said compound has formula Ig:
Figure A2008800104740007C1
R wherein 1, R 2, R 4, R 5, R 6, R 7, R 8With n such as claim 1 definition.
13. according to the described compound of arbitrary claim in the claim 1 to 12 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 4And R 5With R 6And R 7In at least one form randomly through 1-4-Z-R together with its corresponding shared carbon atom 12The C that group replaces 3-14Cycloalkyl, and Z and R 12As defined herein.
14. compound according to claim 13 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 4And R 5Form randomly through 1-4-Z-R together with its shared carbon atom 12The C that group replaces 3-14Cycloalkyl, and Z and R 12Such as claim 1 definition.
15. compound according to claim 14 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 4And R 5Form cyclopropyl or cyclobutyl together with its shared carbon atom.
16. according to the described compound of arbitrary claim in the claim 1 to 15 or its pharmaceutically acceptable salt, hydrate or ester, wherein n is 0.
17. according to the described compound of arbitrary claim in the claim 1 to 16 or its pharmaceutically acceptable salt, hydrate or ester, wherein said compound has formula II:
Figure A2008800104740007C2
R wherein 4And R 5Form randomly through 1-4-Z-R together with its shared carbon atom 12The C that group replaces 3-14Cycloalkyl, and R 1, R 2, R 3, R 3', R 8, R 12With Z such as claim 1 definition.
18. compound according to claim 17 or its pharmaceutically acceptable salt, hydrate or ester, wherein said compound has formula IIg:
Figure A2008800104740008C1
R wherein 1, R 2, R 4, R 5And R 8Such as claim 1 definition.
19. according to the described compound of arbitrary claim in the claim 1 to 15 or its pharmaceutically acceptable salt, hydrate or ester, wherein n is 1.
20. according to the described compound of arbitrary claim in the claim 1 to 18 or its pharmaceutically acceptable salt, hydrate or ester, wherein said compound has formula IVa or formula IVb:
Figure A2008800104740008C2
R wherein 1, R 3, R 3', R 4, R 5, R 6, R 7, R 8With n such as claim 1 definition.
21. according to the described compound of arbitrary claim in the claim 1 to 20 or its pharmaceutically acceptable salt, hydrate or ester, wherein n is 1 and R 6And R 7Be H or C independently 1-6Alkyl, wherein said C 1-6Alkyl is randomly through 1-4-Z-R 12Group replacement and Z and R 12Such as claim 1 definition.
22. according to the described compound of arbitrary claim in the claim 1 to 20 or its pharmaceutically acceptable salt, hydrate or ester, wherein n is 1 and R 6And R 7Form randomly through 1-4-Z-R together with its corresponding shared carbon atom 12The C that group replaces 3-14Cycloalkyl, and Z and R 12Such as claim 1 definition.
23. compound according to claim 22 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 6And R 7Form cyclopropyl or cyclobutyl together with its corresponding shared carbon atom.
24. compound according to claim 22 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 4And R 5Be H or independently randomly through 1-4-Z-R 12The C that group replaces 1-6Alkyl, and Z and R 12Such as claim 1 definition.
25. according to the described compound of arbitrary claim in the claim 1 to 24 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 8For through halogen ,-O-Z-R 13, C 1-10Alkyl or C 1-10The C that alkylhalide group replaces 6-14Aryl, wherein Z and R 13Such as claim 1 definition.
26. compound according to claim 25 or its pharmaceutically acceptable salt, hydrate or ester, wherein R 8For through halogen ,-O-Z-R 13, C 1-10Alkyl or C 1-10The phenyl that alkylhalide group replaces, wherein Z and R 13Such as claim 1 definition.
27. compound according to claim 1, wherein said compound are to be selected from 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethoxy) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-8-ethyl-3-hydroxyquinoline-4-formic acid; 8-sec-butyl-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid; The 8-tertiary butyl-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 8-chloro-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-phenylquinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-8-fluoro-3-hydroxyquinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 8-bromo-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid; And 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6,8-dimethyl quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
28. compound according to claim 1, wherein said compound are to be selected from 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-toluquinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-7-ethyl-3-hydroxyquinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-7-toluquinoline-4-formic acid; 8-ethyl-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 8-sec-butyl-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 7-chloro-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-6-fluoro-3-hydroxyquinoline-4-formic acid; 6-bromo-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-toluquinoline-4-formic acid; And 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6,8-dimethyl quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
29. compound according to claim 1, wherein said compound are to be selected from 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-(trifluoromethoxy) quinoline-4-formic acid; 6-chloro-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3,6-dihydroxyl quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxy-6-isopropylquinoline-4-4-formic acid; 7-chloro-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 6-ethyl-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3,6-dihydroxyl quinoline-4-formic acid; With 6-chloro-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
30. compound according to claim 1, wherein said compound are to be selected from 3-hydroxyl-8-methyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 3-hydroxyl-2-(1-phenycyclopropyl)-6-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-6-methyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 3-hydroxyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-2-(1-phenycyclopropyl)-8-(thiene-3-yl-) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(thiene-3-yl-) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-isopropyl quinoline-4-formic acid; And 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-7,8-dimethyl quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
31. compound according to claim 1, wherein said compound are to be selected from 2-(1-(4-chloro-phenyl-) cyclopropyl)-8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyquinoline-4-formic acid; 3-hydroxyl-2-(1-phenycyclopropyl)-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid; 3-hydroxyl-7,8-dimethyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 3-hydroxyl-8-sec.-propyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 3-hydroxyl-8-phenyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 3-hydroxyl-2-(1-phenycyclopropyl)-8-(trifluoromethoxy) quinoline-4-formic acid; 8-chloro-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 6-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; With 3-hydroxyl-2-(1-(4-p-methoxy-phenyl) cyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
32. compound according to claim 1, wherein said compound are to be selected from 3-hydroxyl-2-(1-(4-p-methoxy-phenyl) cyclopropyl)-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid; 3-hydroxyl-8-(trifluoromethyl)-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid; 2-(1-(4-bromophenyl) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(3-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(2-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-2-(1-(4-(trifluoromethoxy) phenyl) cyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-8-(trifluoromethyl)-2-(1-(3-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclobutyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-2-(1-(thiene-3-yl-) cyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid; With 3-hydroxyl-2-(1-(thiophene-2-yl) cyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
33. compound according to claim 1, wherein said compound are to be selected from 2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-isopropyl quinoline-4-formic acid; 3-hydroxyl-8-(trifluoromethyl)-2-(1-(2-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid; 3-hydroxyl-6,8-dimethyl-2-(1-phenycyclopropyl) quinoline-4-formic acid; 8-ethyl-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 7-ethyl-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 6-chloro-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 7-chloro-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-6,8-dimethyl quinoline-4-formic acid; With 6-ethyl-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
34. compound according to claim 1, wherein said compound are to be selected from 2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-(thiene-3-yl-) quinoline-4-formic acid; 6-bromo-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 8-chloro-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 7-bromo-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 8-bromo-2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyquinoline-4-formic acid; 2-(1-(4-fluorophenyl) cyclopropyl)-8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyquinoline-4-formic acid; 2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-phenylquinoline-4-formic acid; 2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-8-toluquinoline-4-formic acid; 2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-6-methoxy quinoline-4-formic acid; And 2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
35. compound according to claim 1, wherein said compound are to be selected from 2-(1-(4-fluorophenyl) cyclopropyl)-3-hydroxyl-7,8-dimethyl quinoline-4-formic acid; 8-ethyl-2-(1-tolyl cyclopropyl)-3-hydroxyquinoline-4-formic acid; 8-methyl-2-(1-p-methylphenyl cyclopropyl)-3-hydroxyquinoline-4-formic acid; 3-hydroxyl-6,8-dimethyl-2-(1-p-methylphenyl cyclopropyl) quinoline-4-formic acid; 8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyl-2-(1-p-methylphenyl cyclopropyl) quinoline-4-formic acid; 3-hydroxyl-8-sec.-propyl-2-(1-p-methylphenyl cyclopropyl) quinoline-4-formic acid; 8-ethyl-3-hydroxyl-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid; 3-hydroxyl-8-sec.-propyl-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid; 7-ethyl-3-hydroxyl-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid; With 3-hydroxyl-6-(trifluoromethoxy)-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
36. compound according to claim 1, wherein said compound are to be selected from 3-hydroxyl-8-(thiene-3-yl-)-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid; 3-hydroxyl-8-phenyl-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl) quinoline-4-formic acid; 3-hydroxyl-2-(1-(4-(trifluoromethyl) phenyl) cyclopropyl)-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-methyl-8-(trifluoromethyl) quinoline-4-formic acid; 6-chloro-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-6-phenyl-8-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-methyl-6-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl-6-ethyl-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-8-ethyl-3-hydroxyl-6-(trifluoromethyl) quinoline-4-formic acid; And 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-phenyl-6-(trifluoromethyl) quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
37. compound according to claim 1, wherein said compound are to be selected from 3-hydroxyl-6-methyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-6-phenyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid; 6-bromo-2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 6-ethyl-3-hydroxyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-2-(1-(4-chloro-phenyl-) cyclopropyl)-6, two (trifluoromethyl) quinoline of 8--4-formic acid; 2-(1-(4-phenyl) cyclopropyl-3-hydroxyl-6,8-pair-(trifluoromethyl) quinoline-4-formic acid; 6-bromo-3-hydroxyl-2-(1-phenycyclopropyl)-8-(trifluoromethyl) quinoline-4-formic acid; 2-(1-(4-chloro-phenyl-) cyclopropyl)-3-hydroxyquinoline-4, the 8-dioctyl phthalate; 2-(1-(4-chloro-phenyl)-cyclopropyl)-8-cyclopropyl-3-hydroxyl-quinoline-4-formic acid; 8-cyclopropyl-3-hydroxyl-2-(1-phenyl-cyclopropyl)-quinoline-4-formic acid; 3-hydroxyl-2-(1-phenyl-cyclopropyl methyl)-8-fluoroform yl-quinoline-4-formic acid; 2-(1-phenmethyl-cyclopropyl)-3-hydroxyl-8-fluoroform yl-quinoline-4-formic acid; With 3-hydroxyl-7,8-dimethyl-2-(1-p-methylphenyl-cyclopropyl)-quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
38. a compound, it is to be selected from 3-hydroxyl-2-(2-phenyl third-2-yl)-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid; 3-hydroxyl-7,8-dimethyl-2-(2-phenyl third-2-yl) quinoline-4-formic acid; 3-hydroxyl-8-sec.-propyl-2-(2-phenyl third-2-yl) quinoline-4-formic acid; 3-hydroxyl-2-(2-phenyl third-2-yl)-8-(trifluoromethyl) quinoline-4-formic acid; 2-(2-(4-chloro-phenyl-) third-2-yl)-3-hydroxyl-8-isopropyl quinoline-4-formic acid; 2-(2-(4-chloro-phenyl-) third-2-yl)-3-hydroxyl-8-(trifluoromethyl) quinoline-4-formic acid; 2-(2-(4-chloro-phenyl-) third-2-yl)-3-hydroxyl-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid; 2-(2-(4-chloro-phenyl-) third-2-yl)-3-hydroxyl-7,8-dimethyl quinoline-4-formic acid; 2-(2-(4-chloro-phenyl-) third-2-yl)-8-(1,1,1,3,3,3-hexafluoro-2-hydroxyl third-2-yl)-3-hydroxyquinoline-4-formic acid; 3-hydroxyl-2-(1-phenylethyl)-8-(trifluoromethyl) quinoline-4-formic acid; 2-[1-(4-chloro-phenyl-) ethyl]-3-hydroxyl-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid; 3-hydroxyl-2-(1-phenylethyl)-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid; 3-hydroxyl-2-(1-phenyl propyl)-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-7,8-dimethyl-2-(1-phenyl propyl) quinoline-4-formic acid; 3-hydroxyl-2-(2-methyl isophthalic acid-phenyl propyl)-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-8-sec.-propyl-2-(2-methyl isophthalic acid-phenyl propyl) quinoline-4-formic acid; 3-hydroxyl-7,8-dimethyl-2-(2-methyl isophthalic acid-phenyl propyl) quinoline-4-formic acid; 3-hydroxyl-2-(1-phenyl third-2-yl)-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-8-sec.-propyl-2-(1-phenyl third-2-yl) quinoline-4-formic acid; 3-hydroxyl-7,8-dimethyl-2-(1-phenyl third-2-yl) quinoline-4-formic acid; 3-hydroxyl-2-(2-phenyl propyl)-8-(trifluoromethyl) quinoline-4-formic acid; 3-hydroxyl-8-sec.-propyl-2-(2-phenyl propyl) quinoline-4-formic acid; 3-hydroxyl-7,8-dimethyl-2-(2-phenyl propyl) quinoline-4-formic acid; And 2-(4-chlorophenylmethyl)-3-[(morpholine-4-base carbonyl) oxygen base]-7,8,9,10-tetrahydro benzo [h] quinoline-4-formic acid, or its pharmaceutically acceptable salt, hydrate or ester.
39. a medical composition, its comprise the treatment significant quantity according to the described compound of arbitrary claim in the claim 1 to 38 or its pharmaceutically acceptable salt, hydrate or ester and pharmaceutically acceptable supporting agent or vehicle.
40. adherent method in the cell that suppresses to select in the mammalian body plain mediation, its comprise to described Mammals throw with the treatment significant quantity according to the described compound of arbitrary claim in the claim 1 to 38 or its pharmaceutically acceptable salt, hydrate or ester.
41. a treatment or prevent mammiferous thrombotic method, its comprise to described Mammals throw with the treatment significant quantity according to the described compound of arbitrary claim in the claim 1 to 38 or its pharmaceutically acceptable salt, hydrate or ester-formin.
42. method for the treatment of or preventing mammiferous disease or illness, described method comprise to described Mammals throw with the treatment significant quantity according to the described compound of arbitrary claim in the claim 1 to 38 or its pharmaceutically acceptable salt, hydrate or ester-formin, wherein said disease or illness are to be selected from atherosclerosis, the atherosclerosis thrombosis, restenosis, myocardial infarction, ischemia-reperfusion, Raynaud's syndrome (Reynauld ' ssyndrome), the inflammatory enteropathy, osteoarthritis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (chronic obstructive pulmonary disease, COPD), pulmonary emphysema, the lung inflammation, delayed hypersensitivity, idiopathic pulmonary fibrosis, cystic fibrosis, thermal damage, apoplexy, experimental allergic encephalomyelitis (experimental allergic encephalomyelitis), wound Secondary cases multiple organ injury syndromes, neutrophilia tetter (Si Weiteshi disease (Sweet ' s disease)), glomerulonephritis, ulcerative colitis, Crohn disease (Crohn ' s disease), necrotizing enterocolitis, the toxicity of cytokine induction, gingivitis, periodontitis, hemolytic uremic syndrome, psoriasis, systemic lupus erythematosus, the autoimmunity thyroiditis, multiple sclerosis, rheumatoid arthritis, scleritis, Ge Leifushi disease (Grave ' s disease), the immune-mediated side effect of the treatment relevant with hemodialysis or leukopheresis, the granulocyte infusion syndromes of being correlated with, venous thrombosis, syndromes behind the thrombosis, unstable angina, transient ischemic attack, the periphery vascular disease, the transfer relevant with cancer, sicklemia, organ transplant rejection and congestive heart failure.
43. one kind according to the described compound of arbitrary claim in the claim 1 to 38 or its pharmaceutically acceptable salt, the purposes of hydrate or ester-formin, it is used to prepare for treatment or prevents the medicament of mammiferous disease or illness, and wherein said disease or illness are to be selected from atherosclerosis, the atherosclerosis thrombosis, restenosis, myocardial infarction, ischemia-reperfusion, Raynaud's syndrome, the inflammatory enteropathy, osteoarthritis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD), pulmonary emphysema, the lung inflammation, delayed hypersensitivity, idiopathic pulmonary fibrosis, cystic fibrosis, thermal damage, apoplexy, experimental allergic encephalomyelitis, wound Secondary cases multiple organ injury syndromes, neutrophilia tetter (Si Weiteshi disease), glomerulonephritis, ulcerative colitis, Crohn disease, necrotizing enterocolitis, the toxicity of cytokine induction, gingivitis, periodontitis, hemolytic uremic syndrome, psoriasis, systemic lupus erythematosus, the autoimmunity thyroiditis, multiple sclerosis, rheumatoid arthritis, scleritis, the Ge Leifushi disease, the immune-mediated side effect of the treatment relevant with hemodialysis or leukopheresis, the granulocyte infusion syndromes of being correlated with, venous thrombosis, syndromes behind the thrombosis, unstable angina, transient ischemic attack, the periphery vascular disease, the transfer relevant with cancer, sicklemia, organ transplant rejection and congestive heart failure.
CN200880010474A 2007-03-30 2008-03-28 Quinoline derivatives and pharmaceutical compositions comprising them for selectin inhibition Pending CN101646652A (en)

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CN112661636B (en) * 2019-10-16 2024-08-02 信越化学工业株式会社 Acyloxy and hydroxyketone compounds containing 1, 2-trimethyl-3-cyclopentenyl and preparation method thereof

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